Heterocyclic amide derivatives for the treatment of diabetes and other diseases

ABSTRACT

The present invention relates to methods of treating breast cancer, diabetes, and/or related metabolic disorders with certain substituted heterocycles of Formula (200),  
                 
 
wherein B, H, I, J and K together with the Ar 5  form a ring containing at least one amide residue, and W, X, Y and Z together form a 2,4-thiazolidinedione, 2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one residue; or a pharmaceutically acceptable salt thereof.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/384,352, filed Mar. 6, 2003, now allowed, which claimed priority tothe U.S. Provisional Application Ser. No. 60/362,702, filed Mar. 8,2002. The disclosure of all the above-recited parent applications ishereby incorporated herein in their entirety by this reference.

BACKGROUND OF THE INVENTION

Type 2 diabetes also referred to as non-insulin dependent diabetesmellitus (NIDDM), afflicts between 80 and 90% of all diabetic patientsin developed countries. In the United States alone, approximately 15million people, and more than 100 million worldwide, are affected.Because this disorder is a late onset disease and occurs often inoverweight persons, it can be expected that the number of patientssuffering from this disease will increase further. Patients sufferingfrom type 2 diabetes usually still produce insulin but becomeincreasingly resistant to their own insulin and to insulin therapy.

A new class of drugs has been recently introduced that resensitizespatients to their own insulin (insulin sensitizers), thereby reducingblood glucose and triglyceride levels, and thus abolishing, or at leastreducing, the requirement for exogenous insulin. Troglitazone (Resulin™)and rosiglitazone (Avandia™) were among the first representatives ofthis class of drugs approved for the treatment of type 2 diabetes in theUnited States and several other countries. The currently approvedcompounds can however have side effects including rare but severe livertoxicities and they can increase body weight in humans. Such sideeffects are of major concern for diabetes patients who can requiretreatment for a decade or longer. Therefore, new and better drugs forthe treatment of type 2 diabetes and related disorders are needed. Inparticular, drugs that can control blood sugar levels and simultaneouslycontrol hyperlipidemia and hypercholesterolemia are desirable. Elevatedlevels of cholesterol lead to atherosclerosis and heart disease which inmany type 2 diabetes patients is the cause of death.

There is also a need for the more effective drugs to treat diseases ofuncontrolled cellular proliferation, such as cancers. Certain moleculesthat have strong cellular differentiation activity can inhibit theuncontrolled cellular proliferation of cancer cells, in particularbreast cancer.

Small molecules that can be effective for the treatment of diabetesand/or disorders of carbohydrate metabolism were disclosed in U.S. Pat.No. 6,515,003, issued Feb. 4, 2003, based on U.S. patent applicationSer. No. 09/652,810, filed Aug. 31, 2000, which claimed priority to U.S.Provisional Patent Application 60/151,670, filed Aug. 31, 1999. Relatedsmall molecules that can be useful in the treatment of certain cancerswere disclosed in PCT Patent Application WO 01/16122, published Mar. 8,2001, which claimed priority to the same U.S. Provisional PatentApplication 60/151,670 cited above. The disclosures of all theabove-described patent documents are hereby incorporated herein by thisreference, for both their chemical structural disclosures, theirteachings of the biological activities of those compounds, and methodsfor their use as pharmaceutical compositions.

There is however a continuing need for effective drugs for the treatmentof cancers, and for the treatment of type 2 diabetes and associateddisorders of carbohydrate and/or lipid metabolism, includinghyperlipidemia and hypercholesterolemia. In particular, there is acontinuing need new drugs that can control the blood sugar levels ofdiabetics, and simultaneously control hyperlipidemia andhypercholesterolemia so as to lessen or prevent atherosclerosis.

SUMMARY OF THE INVENTION

Some embodiments of the invention relate to heterocyclic compoundshaving the structure:

wherein

-   -   a) Ar₅ is an aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;    -   b) B, H, I, J and K are independently selected from —C(O)—,        —C(S)—, —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—,        —C(R₁₀₅)(R₁₀₆)—, or —C(R₁₀₇)(R₁₀₈)—, wherein one, or two of B,        H, I, J or K can optionally be absent; and        -   i) R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇ and R₁₀₈ are            independently selected from hydrogen, hydroxyl, a halogen,            amino, or an organic radical;        -   ii) two of B, H, I, J and K form at least one radical having            the structure:        -    wherein R_(x) is a R₁₀₁ or R₁₀₂ radical;        -   iii) Ar₅ together with B, H, I, J and K comprise from 2 to            24 carbon atoms;    -   c) Ar₆ is an aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;    -   d) R₁₀₉ is hydrogen, hydroxy, or an organic radical;    -   e) ----- is either present or absent;    -   f) HAr is a heterocycle having the structure:

or a pharmaceutically acceptable salt thereof.

As can be seen from the above description, the compounds of theinvention have a heterocyclic ring comprising B, H, I, J and K residues,wherein the heterocyclic ring comprises an amide residue having thestructure:

The heterocyclic amide compounds comprising an amide residue have beenfound to be unexpectedly active for advantageously regulatingcarbohydrate metabolism, including serum glucose levels. Theheterocyclic amide compounds have also been found to be unexpectedlyeffective modulators of lipid metabolism, and are therefore useful forthe treatment of hyperlipidemia and/or hypercholesterdemia. Therefore,the heterocyclic amide compounds of the invention can simultaneously andbeneficially regulate carbohydrate and lipid metabolism so as tosimultaneously decrease levels of serum glucose, serum triglycerides,and serum cholesterol. As a result, it has been found that theheterocyclic amide compounds are unexpectedly useful for the treatmentof type 2 diabetes and the simultaneous treatment of the hyperlipidemia,hypercholesterdemia, and/or atherosclerosis which is often associatedwith diabetes. The heterocyclic amide compounds of the invention havealso been found to have unexpectedly superior pharmaceutical properties,including unexpectedly superior oral bioavailability as compared toprior art compounds.

The heterocyclic compounds of the present invention also show activityfor inducing adipocyte differentiation in certain well known cell linesof pre-adipocytes. The ability of a compound to induce differentiationof these cell lines is also known to correlate with anticancer activity.As a result, the heterocyclic compounds of the invention have beentested for utility in the treatment of diseases of uncontrolledproliferation. The heterocyclic compound described herein have shownunexpectedly effective results for the treatment of breast cancer in anin vivo rat model of breast cancer.

Further embodiments of the amide compounds of the invention, andpharmaceutical compositions comprising one or more of the compounds ofthe invention will be described in more detail in the specification andwritten description hereinbelow. Other embodiments of the inventionrelate to methods of synthesizing the amide compounds disclosed herein.

The invention also provides methods for the treatment of diabetes andassociated diseases, as well as methods for the treatment of diseases ofuncontrolled cellular proliferation comprising administering to a mammaldiagnosed as having a disease of uncontrolled cellular proliferation oneor more compounds of the invention, or a pharmaceutical compositionthereof.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of in-vitro screening assays for the ability ofsome of the compounds of the invention to induce differentiation of3T3-L1 pre-adipocytes to adipocytes.

FIGS. 2 a-d show the ability of certain compounds 1, 2, 11, 13, and 25,when orally administered, to simultaneously decrease the serum glucoseand triglyceride levels of KKA^(y) mice, as compared to control KKA^(y)mice that do not receive the compounds.

FIG. 2 e shows the ability of compound 25, when orally administered, tosimultaneously decrease the serum glucose, serum triglyceride, and serumcholesterol levels of KKA^(y) mice at various dosage levels, as comparedto control KKA^(y) mice that do not receive the compound.

FIG. 3 shows the glucose and triglyceride lowering activity of compound25 in the type 2 diabetic db/db Mouse Model.

FIG. 4 shows the ability of compound 2 to increase cholesterol effluxfrom macrophage cells.

FIG. 5 a-c show the ability of compounds 2, 6, and 25 to decrease totalcholesterol and LDL (bad cholesterol) while increasing HDL (goodcholesterol) in Sprague Dawley rats.

FIG. 6 shows the ability of the compounds to decrease the number ofprogressing carcinogen induced mammary tumors in Sprague Dawley rats,and increase the number of static and regressing tumors.

FIG. 7 shows the unexpectedly improved oral bioavailability of compound25 compared to comparative compound 24.

FIG. 8 shows examples of methods for synthesizing precancers of thecompounds disclosed herein.

FIG. 9 shows examples of methods for synthesizing the compoundsdisclosed herein.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of various embodiments of the inventionand the Examples included therein and to the Figures and their previousand following description. Before the present compounds, compositions,and/or methods are disclosed and described, it is to be understood thatthis invention is not limited to specific synthetic methods, specificpharmaceutical carriers or formulations, or to particular modes ofadministering the compounds of the invention, as such can, of course,vary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only and is notintended to be limiting.

The present invention provides heterocyclic amide compounds that areuseful, for example, to modulate lipid and/or carbohydrate metabolism,and especially for the treatment of diabetes, such as type 2 diabetes,and other diseases. In addition, compounds of the invention havedemonstrated unexpectedly superior oral bioavailability, as exhibited bytheir high blood levels after oral dosing in animals. Oralbioavailability allows oral dosing for use in chronic diseases, with theadvantage of self-administration and decreased cost over other means ofadministration. The compounds described herein can be used effectivelyto prevent, alleviate or otherwise treat type 2 diabetes and/or otherdisease states in mammals and/or humans, such as atherosclerosis anddiseases related to inflammation and/or uncontrolled proliferation,including cancers such as breast cancer.

Definitions

In the specification and Formulae described herein the following termsare hereby defined.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not. For example, the phrase “optionally substituted lower alkyl”means that the lower alkyl group may or may not be substituted and thatthe description includes both unsubstituted lower alkyl and lower alkylswhere there is substitution.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an aromatic compound” includes mixtures of aromaticcompounds.

Often, ranges are expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms another embodiment. Itwill be further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material can beadministered to an individual along with the relevant active compoundwithout causing clinically unacceptable biological effects orinteracting in a deleterious manner with any of the other components ofthe pharmaceutical composition in which it is contained.

I By the term “effective amount” of a compound as provided herein ismeant a sufficient amount of the compound to provide the desiredregulation of a desired function, such as gene expression, proteinfunction, or a disease condition. As will be pointed out below, theexact amount required will vary from subject to subject, depending onthe species, age, and general condition of the subject, the severity ofthe disease that is being treated, the particular compound used, itsmode of administration, and the like. Thus, it is not possible tospecify an exact “effective amount.” However, an appropriate effectiveamount can be determined by one of ordinary skill in the art using onlyroutine experimentation.

The term “alkyl” denotes a hydrocarbon group or residue which isstructurally similar to a non-cyclic alkane compound modified by theremoval of one hydrogen from the non-cyclic alkane and the substitutiontherefore of a non-hydrogen group or residue. Alkyls comprise anoncyclic, saturated, straight or branched chain hydrocarbon residuehaving from 1 to 12 carbons, or 1 to 8 carbons, or 1 to 6 carbons.Examples of such alkyl radicals include methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, t-butyl, amyl, t-amyl, n-pentyl and thelike. Lower alkyls comprise a noncyclic, saturated, straight or branchedchain hydrocarbon residue having from 1 to 4 carbon atoms.

The term “substituted alkyl” denotes an alkyl radical analogous to theabove definition that is further substituted with one, two, or moreadditional organic or inorganic substituent groups. Suitable substituentgroups include but are not limited to hydroxyl, cycloalkyl, amino,mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano,carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl,alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy,haloalkoxy, heteroaryl, substituted heteroaryl, aryl or substitutedaryl. When more than one substituent group is present then they can bethe same or different. The organic substituent groups can comprise from1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbonatoms.

The term “alkenyl” denotes an alkyl residue as defined above thatcomprises at least one carbon-carbon double bond. Examples include butare not limited to vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and the like.The term “alkenyl” includes dienes and trienes of straight and branchchains.

The term “substituted alkenyl” denotes an alkenyl residue as definedabove definitions that is substituted with one or more groups, butpreferably one, two or three groups, selected from halogen, hydroxyl,cycloalkyl, amino, mono-substituted amino, di-substituted amino,acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy. When more thanone group is present then they can be the same or different. The organicsubstituent groups can comprise from 1 to 12 carbon atoms, or from 1 to6 carbon atoms, or from 1 to 4 carbon atoms.

The term “alkynyl” denotes a residue as defined above that comprises atleast one carbon-carbon double bond. Examples include but are notlimited ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl-3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term “alkynyl”includes di- and tri-ynes.

The term “substituted alkynyl” denotes an alkylnyl residue of the abovedefinition that is substituted with one or more groups, but preferablyone or two groups, selected from halogen, hydroxyl, cycloalkyl, amino,mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano,carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl,alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy orhaloalkoxy. When more than one group is present then they can be thesame or different. The organic substituent groups can comprise from 1 to12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbonatoms.

The term “cycloalkyl” denotes a hydrocarbon group or residue which isstructurally similar to a cyclic alkane compound modified by the removalof one hydrogen from the cyclic alkane and substitution therefore of anon-hydrogen group or residue. Cycloalkyl groups, or residues radicalcontain 3 to 18 carbons, or preferably 4 to 12 carbons, or 5 to 8carbons. Examples include as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, decahydronapthyl, adamantyl, and like residues.

The term “substituted cycloalkyl” denotes a cycloalkyl residue asdefined above that is further substituted with one, two, or moreadditional organic or inorganic groups that can include but are notlimited to halogen, alkyl, substituted alkyl, hydroxyl, alkoxy,substituted alkoxy, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,amino, mono-substituted amino or di-substituted amino. When thecycloalkyl is substituted with more than one substituent group, they canbe the same or different. The organic substituent groups can comprisefrom 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4carbon atoms.

The term “cycloalkenyl” denotes a cycloalkyl radical as defined abovethat comprises at least one carbon-carbon double bond. Examples includebut are not limited to cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl,1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexyl,2-cyclohexyl, 3-cyclohexyl and the like. The term “substitutedcycloalkenyl” denotes a cycloalkyl as defined above further substitutedwith one or more groups selected from halogen, alkyl, hydroxyl, alkoxy,substituted alkoxy, haloalkoxy, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide, amino, mono-substituted amino or di-substitutedamino. When the cycloalkenyl is substituted with more than one group,they can be the same or different. The organic substituent groups cancomprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from1 to 4 carbon atoms.

The term “alkoxy” as used herein denotes an alkyl residue, definedabove, attached directly to a oxygen to form an ether residue. Examplesinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy,iso-butoxy and the like.

The term “substituted alkoxy” denotes an alkoxy residue of the abovedefinition that is substituted with one or more substituent groups, butpreferably one or two groups, which include but are not limited tohydroxyl, cycloalkyl, amino, mono-substituted amino, di-substitutedamino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy. When more thanone group is present then they can be the same or different. The organicsubstituent groups can comprise from 1 to 12 carbon atoms, or from 1 to6 carbon atoms, or from 1 to 4 carbon atoms.

The term “mono-substituted amino” denotes an amino substituted with oneorganic substituent groups, which include but are not limited to alkyl,substituted alkyl or arylalkyl wherein the terms have the samedefinitions found hereinabove.

The term “di-substituted amino” denotes an amino residue substitutedwith two radicals that can be same or different selected from aryl,substituted aryl, alkyl, substituted alkyl or arylalkyl wherein theterms have the same definitions found throughout. Some examples includedimethylamino, methylethylamino, diethylamino and the like.

The term “haloalkyl” denotes a alkyl residue as defined above,substituted with one or more halogens, preferably fluorine, such as atrifluoromethyl, pentafluoroethyl and the like.

The term “haloalkoxy” denotes a haloalkyl residue as defined above, thatis directly attached to an oxygen to form trifluoromethoxy,pentafluoroethoxy and the like.

The term “acyl” denotes a R—C(O)— residue containing 1 to 8 carbons.Examples include but are not limited to formyl, acetyl, propionyl,butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and thelike.

The term “acyloxy” denotes a an acyl radical as defined above directlyattached to an oxygen to form an R—C(O)O— residue. Examples include butare not limited to acetyloxy, propionyloxy, butanoyloxy,iso-butanoyloxy, benzoyloxy and the like.

The term “aryl” denotes a ring radical containing 6 to 18 carbons, orpreferably 6 to 12 carbons, having at least one six-membered aromatic“benzene” residue therein. Examples of such aryl radicals include phenyland naphthyl. The term “substituted aryl” denotes an aryl ring radicalas defined above that is substituted with one or more, or preferably 1,2, or 3 organic or inorganic substituent groups, which include but arenot limited to a halogen, alkyl, substituted alkyl, hydroxyl,cycloalkyl, amino, mono-substituted amino, di-substituted amino,acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy, aryl,substituted aryl, heteroaryl, heterocyclic ring, substitutedheterocyclic ring wherein the terms are defined herein. The organicsubstituent groups can comprise from 1 to 12 carbon atoms, or from 1 to6 carbon atoms, or from 1 to 4 carbon atoms.

The term “heteroaryl” denotes an aryl ring radical as defined above,wherein at least one of the carbons, or preferably 1, 2, or 3 carbons ofthe aryl aromatic ring has been replaced with a heteroatom, whichinclude but are not limited to nitrogen, oxygen, and sulfur atoms.Examples of heteroaryl residues include pyridyl, bipyridyl, furanyl, andthiofuranyl residues. Substituted “heteroaryl” residues can have one ormore organic or inorganic substituent groups, or preferably 1, 2, or 3such groups, as referred to herein-above for aryl groups, bound to thecarbon atoms of the heteroaromatic rings. The organic substituent groupscan comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, orfrom 1 to 4 carbon atoms.

The term “halo” or “halogen” refers to a fluoro, chloro, bromo or iodogroup.

The term “thioalkyl” denotes a sulfide radical containing 1 to 8carbons, linear or branched. Examples include methylsulfide, ethylsulfide, isopropylsulfide and the like.

The term “thiohaloalkyl” denotes a thioalkyl radical substituted withone or more halogens. Examples include trifluoromethylthio,1,1-difluoroethylthio, 2,2,2-trifluoroethylthio and the like.

The term “carboalkoxy” refers to an alkyl ester of a carboxylic acid,wherein alkyl has the same definition as found above. Examples includecarbomethoxy, carboethoxy, carboisopropoxy and the like.

The term “alkylcarboxamide” denotes a single alkyl-group attached to theamine of an amide, wherein alkyl has the same definition as found above.Examples include N-methylcarboxamide, N-ethylcarboxamide,N-(iso-propyl)carboxamide and the like. The term “substitutedalkylcarboxamide” denotes a single “substituted alkyl” group, as definedabove, attached to the amine of an amide.

The term “dialkylcarboxamide” denotes two alkyl or arylalkyl groups thatare the same or different attached to the amine of an amide, whereinalkyl has the same definition as found above. Examples of adialkylcarboxamide include N,N-dimethylcarboxamide,N-methyl-N-ethylcarboxamide and the like. The term “substituteddialkylcarboxamide” denotes two alkyl groups attached to the amine of anamide, where one or both groups is a “substituted alkyl”, as definedabove. It is understood that these groups can be the same or different.Examples include N,N-dibenzylcarboxamide, N-benzyl-N-methylcarboxamideand the like.

The term “arylalkyl” defines an alkylene, such as —CH₂— for example,which is substituted with an aryl group that can be substituted orunsubstituted as defined above. Examples of an “arylalkyl” includebenzyl, phenethylene and the like.

A residue of a chemical species, as used in the specification andconcluding claims, refers to a structural fragment, or a moiety that isthe resulting product of the chemical species in a particular reactionscheme or subsequent formulation or chemical product, regardless ofwhether the structural fragment or moiety is actually obtained from thechemical species. Thus, an ethylene glycol residue in a polyester refersto one or more —OCH₂CH₂O— repeat units in the polyester, regardless ofwhether ethylene glycol is used to prepare the polyester. Similarly, a2,4-thiazolidinedione residue in a chemical compound refers to one ormore -2,4-thiazolidinedione moieties of the compound, regardless ofwhether the residue was obtained by reacting 2,4-thiazolidinedione toobtain the compound.

The term “organic residue” defines a carbon containing residue, i.e. aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic resides can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1 to 4carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has the structure

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Inorganic radicals,” as the term is defined and used herein contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

“Organic radicals” as the term is defined and used herein contain one ormore carbon atoms. An organic radical can have, for example, 1-26 carbonatoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, or 1-4carbon atoms. Organic radicals often have hydrogen bound to at leastsome of the carbon atoms of the organic radical. One example, of anorganic radical that comprises no inorganic atoms is a5,6,7,8-tetrahydro-2-naphthyl radical. In some embodiments, an organicradical can contain 1-10 inorganic heteroatoms bound thereto or therein,including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.Examples of organic radicals include but are not limited to an alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substitutedamino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxaamide, alkylsulfonyl, alkylsulfinyl,thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl,haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, orsubstituted heterocyclic radicals, wherein the terms are definedelsewhere herein. A few non-limiting examples of organic radicals thatinclude heteroatoms include alkoxy radicals, trifluoromethoxy radicals,acetoxy radicals, dimethylamino radicals and the like.

The term “amide” as defined hereby and used in the instant specificationrefers to a functional group or residue that contains a carbonyl (CO)group bound to a nitrogen atom, i.e. a residue having the formula:

It is to be understood that for the purposes, of this disclosure and theaccompanying claims, any molecule or compound that comprises the abovefunctional group or reside can be termed an amide, regardless of theidentity of the three unspecified substituent groups. For example, ifthe carbonyl carbon and one of the unspecified nitrogen substituents arebound to carbon atoms, the resulting compound would be described hereinas an “amide.” Nevertheless, if the substituent of the carbonyl groupwere a 2^(nd) nitrogen atom, as shown below, the resulting compoundwould still be termed an “amide” herein, even though many of ordinaryskill in the art might often use a more specific term, such as “urea.”Similarly, if the substituent of the carbonyl group were an oxygen atom,the compound would still be termed an amide herein, even though the morespecific term “urethane” might alternatively be employed.

COMPOUNDS OF THE INVENTION

Some disclosed embodiments of the invention relate to a genus ofcompounds of Formula (200):

wherein:

-   -   a) the B, H, I, J and K residues are independently selected from        —C(O)—, —C(S)—, —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—,        —C(R₁₀₅)(R₁₀₆)—, or —C(R₁₀₇)(R₁₀₈)— residues, and from zero to        two of the B, H, I, J or K residues can be absent; wherein:        -   i) R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇ and R₁₀₈ are            independently selected from hydrogen, hydroxyl, a halogen,            amino, or an organic residue comprising 1 to 12 carbon            atoms; or two of the R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆,            R₁₀₇ and R₁₀₈ residues can be connected together to form an            exocyclic substituent residue comprising 1 to 6 ring carbon            atoms and from 0 to 3 optional ring heteroatoms selected            from O, S, or N; and        -   ii) B, H, I, J and K together with the Ar₅ form a ring            containing at least one amide residue having the formula        -    wherein R_(x) is a R₁₀₁ or R₁₀₂ residue;    -   b) Ar₅ is an aryl, substituted aryl, heteroaryl, or substituted        heteroaryl residue comprising from 3 to 6 ring carbon atoms and        from 0 to 3 optional ring heteroatoms selected from O, S, or N;    -   c) Ar₆ is an aryl, substituted aryl, heteroaryl, or substituted        heteroaryl residue comprising from 2 to 6 ring carbon atoms and        from 0 to 3 optional ring heteroatoms selected from O, S, or N;    -   d) R₁₀₉ is hydrogen, hydroxy, or an organic residue comprising 1        to 10 carbon atoms;    -   e) ----- is either present or absent;    -   f) W, X, Y and Z are independently or together —C(O)—, —C(S)—,        —S—, —O— or —NH—, to form a 2,4-thiazolidinedione,        2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or        2-thioxo-imidazolidine-4-one residue; or

a pharmaceutically acceptable salt thereof.

In the embodiments described immediately above, the W, X, Y and Zradicals, together with a carbon atom, form one of four separate fivemembered heterocycles, selected from a 2,4-thiazolidinedione,2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or2-thioxo-imidazolidine-4-one residue, as shown in the drawing below:

For purposes of ease of reference and brevity, the2,4-thiazolidinedione, 2-thioxothiazolidine-4-one,2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one heterocyclicresidues can be generically termed an “HAr” heterocyclic residue orradical. When the “HAr” terminology is employed, an alternativedescription embodying the invention, which is closely related to thegenus of compounds of formula 200 described above can be recited. Thisalternative description relates to a genus of compounds having thestructure

wherein

-   -   a) Ar₅ is an aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;    -   b) B, H, I, J and K are independently selected from —C(O)—,        —C(S)—, —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—,        —C(R₁₀₅)(R₁₀₆)—, or —C(R₁₀₇)(R₁₀₈)—, wherein one, or two of B,        H, I, J or K can optionally be absent; and        -   i) R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇ and R₁₀₈ are            independently selected from hydrogen, hydroxyl, a halogen,            amino, or an organic radical comprising 1 to 12 carbon            atoms;        -   ii) two of B, H, I, J and K form at least one radical having            the structure        -    wherein R_(x) is a R₁₀₁ or R₁₀₂ radical;        -   iii) Ar₅ together with B, H, I, J and K comprise from 2 to            24 carbon atoms;    -   c) Ar₆ is an aryl, substituted aryl, heteroaryl, or substituted        heteroaryl comprising from 2 to 18 carbon atoms;    -   d) R₁₀₉ is hydrogen, hydroxy, or an organic radical comprising 1        to 10 carbon atoms;    -   e) ----- is either present or absent;    -   f) HAr is a heterocycle having the structure

or a pharmaceutically acceptable salt thereof.

The detailed description of the preferred embodiments recited below isintended to be applicable, to the extent reasonably possible, to eitherof the two alternative descriptions of the compounds of the inventioncited immediately above.

Ar₅ is an aryl, substituted aryl, heteroaryl, or substituted heteroarylresidue or radical. As noted in the accompanying definitions, arylradicals have at least one six-membered aromatic “benzene” residuetherein, although additional aromatic rings might be attached thereto,so as to form, for example, a naphthalene or biphenyl radical. The arylring residues are bonded to the Ar₆ radical, and have bonded thereto anon-aromatic ring residue comprising one or more of the B, H, I, J and Kresidues. In many embodiments, Ar₅ is a benzene radical, which can beoptionally additionally substituted with one or more additional organicor inorganic radicals or residues.

Ar₅ can also comprise a heteroaryl radical or residue, wherein the termis defined elsewhere herein. The heteroaryl ring residue is bonded tothe Ar₆ radical and a non-aromatic heterocyclic ring residue comprisingone or more of the B, H, I, J and K residues. In many embodiments, Ar₅comprises a pyridine, pyrimidine, or pyrazine ring.

The aryl or heteroaryl ring residues can optionally and additionallyhave one, two, or more additional substituent residues or radicalsbonded to the aryl or heteroaryl rings, so as to comprise a “substitutedaryl” or “substituted heteroaryl” residue or radical, as the terms aredefined elsewhere herein. The additional substituents can be selectedfrom organic residues, inorganic radicals, or organic radicals as thoseterms are defined elsewhere herein. In some embodiments, the Ar₅ aryl orheteroaryl ring is substituted with one or two additional substituentsindependently selected from a halogen, an amino, or a radical comprising1 to 4 carbon atoms selected from an alkyl, a monosubstituted amino, adisubstituted amino, an alkoxy, or a haloalkoxy.

In some embodiments, Ar₅ is a benzene ring, optionally substituted withone additional substituent selected from a halogen, an amino, or aradical comprising 1 to 4 carbon atoms selected from an alkyl, amonosubstituted amino, a disubstituted amino, an alkoxy, or ahaloalkoxy. An example of a substituted Ar₅ radical comprising a benzenering and one additional substituent would be a radical having thestructure shown below, wherein R_(a) is the additional substituentresidue or radical.

As is also shown in the drawing immediately above, and elsewhere herein,the Ar₅ radical is also bonded to a non-aromatic heterocyclic ringresidue comprising one or more of the B, H, I, J and K residues, whereinthe non-aromatic heterocyclic ring residue is bound to adjacent carbonatoms on the Ar₅ aryl or heteroaryl ring. One or two of the B, H, I, Jand K residues can optionally be absent. Therefore, the non-aromaticheterocyclic ring residue can form five, six, or seven membered rings,wherein the carbons that are part of the Ar₅ aryl or heteroaryl ring arealso considered to be part of the non-aromatic heterocyclic ringresidue.

The B, H, I, J and K residues are independently selected from —C(O)—,—C(S)—, —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—,—C(R₁₀₅)(R₁₀₆)—, or —C(R₁₀₇)(R₁₀₈)— residues, with the proviso that twoof B, H, I, J and K must form an amide residue, as will be furtherdiscussed below. R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇ and R₁₀₈ canbe independently selected from hydrogen, hydroxyl, a halogen, amino, oran organic radicals. In many embodiments, suitable organic radicals forR₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇ and R₁₀₈ comprise 1 to 12carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In someembodiments, lower alkyl radicals such as methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, and t-butyl are particularly suitable R₁₀₁,R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇ or R₁₀₈ substituents.

Although not wishing to be bound by theory, the heterocyclic amidecompounds of the invention, including the Ar₅ radical together with thenon-aromatic heterocyclic ring residue and any additional substituentradicals for Ar₅ are selected so that the Ar₅ radical has a geometry,size, and polarity that is suitable to allow the compounds of theinvention to interact with and substantially fill, yet fit within thebinding regions of the target biological molecules, so as to contributeto the effective binding of the compounds to the binding sites in thebiological target molecules. Therefore, in some embodiments, the Ar₅radical, together with the non-aromatic heterocyclic ring residue andany additional substituent radicals for Ar₅ comprises from 2 to 24carbon atoms, or from 3 to 20 carbon atoms, or from 4 to 18 carbonatoms, or from 5 to 16 carbon atoms.

It must be noted that for all the compounds of the invention, the B, H,I, J and K residues together with the Ar₅ form a non-aromaticheterocyclic ring containing at least one amide residue. The amideresidues as defined elsewhere herein for the purposes of this disclosurehave the structure indicated below, wherein Rx is a R₁₀₁ or R₁₀₂residue.

The amide residue is contained within the non-aromatic heterocyclic ringcomprising B, H, I, J and K. Therefore, in one embodiment of theinvention, ring radical comprising the Ar₅ ring and the non-aromaticheterocyclic ring comprising B, H, I, J and K would have the structureshown immediately below:

wherein R_(x) is a R₁₀₁ or R₁₀₂ residue. In such embodiments, the J atomor residue could be one of several alternatives. If the J atom orresidue was a —C(R₁₀₃)(R₁₀₄)— residue, the resulting structure would be:

Such cyclic compounds comprising an amide group whose carbonyl carbon isbound to another carbon are often termed “lactams.”

Alternatively, if J is an oxygen atom, the resulting compounds aretermed “cyclic carbamates”, and would have the structure:

If the J atom or residue is an —N(R₁₀₂)— residue, the resultingcompounds are termed a “cyclic urea,” and would have the structure:

It is to be understood that in the various embodiments described above,0, 1, or 2, of the B, H, I, J or K residues could be absent. Typicallythe B and K residues are bound to two adjacent carbon atoms on the Ar₅aryl or heteroaryl ring. Therefore the ring comprising the B, H, I, Jand K residues often comprise 5, 6, or 7 ring atoms and the B, H, I, Jand K residues form at least one amide residue.

In some embodiments B, H, I, J and K together with Ar₅ form a ringcontaining at least one amide residue having one of the Formulas(205a-k) wherein Ar₅ is benzene or a substituted benzene radical.Similar structures can also be formed where Ar₅ is a heteroaryl, such aspyridine, pyrimidene, pyrazine, and the like:

In the drawing above, R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈,R₁₁₀, R₁₁₁ or R₁₁₂ can be independently selected from inorganicsubstituents, which include but are not limited to inorganicsubstituents such as hydrogen, halogen, cyano, nitro, hydroxyl, oramino. R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈, R₁₁₀, R₁₁₁ orR₁₁₂ can also be independently selected from organic residues or organicradicals, as those terms are defined elsewhere herein. Examples ofsuitable organic residues or radicals include but are not limited to analkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, acyloxy, amino, mono-substituted amino,di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea,arylurea, alkylcarbamate, arylcarbamate, aryl, heteroaryl, alkoxy,substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy,carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,dialkylcarboxamide or substituted dialkylcarboxamide residue. In someembodiments, preferred R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈,R₁₁₀, R₁₁₁ or R₁₁₂ groups are an alkyl, substituted alkyl, haloalkyl,alkoxy, substituted alkoxy, or haloalkoxy residues, particularly thosecomprising from 1 to 12 carbons, 1 to 6 carbons, or I to four carbons.

In some embodiments, the residue bonded to the nitrogen atom of theamide groups (i.e. R₁₀₁ or R₁₀₂) can hydrogen or an organic radicalcomprising 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbonatoms. In some embodiments, R₁₀₁ or R₁₀₂ is a lower alkyl group, such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In someembodiments, methyl, ethyl, or i-propyl radicals are preferred R₁₀₁ orR₁₀₂ residues.

Some embodiments of the invention relate to lactam compounds of Formula(206):

Some embodiments of the invention relate to lactam compounds of Formula(207):

Some embodiments of the invention relate to compounds of Formula (208):

In some embodiments R₁₀₁ is hydrogen, alkyl or substituted alkyl. Someexamples R₁₀₁ is a straight or branched alkyl of C₁-C₁₂. In otherexamples R₁₀₁ is a straight or branched alkyl of C₁-C₈. In still otherexamples R₁₀₁ is a straight or branched alkyl of C₁-C₆. In yet otherexamples R₁₀₁ is a straight or branched alkyl of C₁-C₄.

Some embodiments of the invention relate to compounds of Formula (200)wherein the two R substituents of —C(R₁₀₃)(R₁₀₄)—, —C(R₁₀₅)(R₁₀₆)—, or—C(R₁₀₇)(R₁₀₈)—, together form an exocyclic cycloalkyl ring, which canoptionally contain O, S or N-alkyl atom groups within the ring. In manyembodiments, the exocyclic cycloalkyl ring comprises from 3 to 6 ringcarbon atoms. Representative examples include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl exocyclic rings. Representative examples ofcompounds comprising, a five membered lactam ring wherein—C(R₁₀₃)(R₁₀₄)— together form an exocyclic cycloalkyl, include those ofFormulae (209a-c).

One or two of the carbons of the exocyclic rings could optionally bereplaced with an O, S or N-alkyl residue, to form tetrahydrofuranyl,tetrahydropyrrolidinyl, and tetrahydrothiofuranyl and like exocyclicring radicals.

Some embodiments of the invention relate to compounds wherein—C(R₁₀₅)(R₁₀₆)— form an exocyclic cycloalkyl optionally substituted withO, S or N-alkyl. Representative examples of compounds for (205b) wherein—C(R₁₀₃)(R₁₀₄)— together form a cycloalkyl optionally substituted withO, S or N-alkyl include those of Formulae (209d-f).

Some embodiments of the invention relate to compounds of Formula (200)wherein —C(R₁₀₇)(R₁₀₈)— form a cycloalkyl optionally substituted with O,S or N-alkyl.

Some embodiments of the invention relate to compounds of Formula (200)where —C(R₁₀₃)(R₁₀₄)—, —C(R₁₀₅)(R₁₀₆)— and —C(R₁₀₇)(R₁₀₈)— independentlyform a cycloalkyl optionally substituted with O, S or N-alkyl.

In some embodiments R₁₀₁ is a substituted alkyl that include aryl alkyl,substituted-aryl alkyl and heteroaryl alkyl. Some representativeexamples are of the Formulae-(210a-b):

wherein R₁₁₅, R₁₁₆, R₁₁₇, R₁₁₈ and R₁₁₉ are independently or togetherhydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl,acyloxy, amino, mono-substituted amino, di-substituted amino,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy,thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide or substituteddialkylcarboxamide; and N, represent the number of nitrogen in the ringwherein x is 1, 2 or 3 thus forming a substituted or unsubstitutedpyridyl, pyrimidinyl or triazinyl respectively.

In some embodiments R₁₀₁ is a substituted alkyl that include heteroarylalkyl. Some interesting heteroaryl residues are five membered rings,some examples include, but are not limited to those of the Formulae(212a-x):

wherein R₁₁₅, R₁₁₆, R₁₁₇, R₁₁₈ and R₁₁₉ are independently or togetherhydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl,acyloxy, amino, mono-substituted amino, di-substituted amino,alkylsulfonamide, substituted alkylsulfonamide, arylsulfonamide,heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl,substituted acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate,substituted alkylthiocarbamate, arylthiocarbamate, heteroaryl,substituted heteroaryl, alkoxy, substituted alkoxy, haloalkoxy,thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy,carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,dialkylcarboxamide or substituted dialkylcarboxamide.

It is understood that compounds of Formula (200) possessing heteroarylresidues wherein N—R₂₂₂ is a hydrogen, that tautomers are possible andare within the scope of the invention. For example, triazole (212e) canexist in several tautomeric forms when R₁₁₇ is hydrogen. These forms canbe represented as shown:

Other represented structures that can exist as various tautomeric formsinclude, for example, (212i), (212m), (212t) and (212u).

The compounds of the invention comprise an Ar₆ ring radical which is anaryl, substituted aryl, heteroaryl, or substituted heteroaryl residue,as those terms are defined elsewhere herein. Ar₆ is bonded to thearomatic ring of Ar₅, and to a carbon atom that bridges and is bonded tothe HAr heterocycle.

The atoms comprising the aromatic ring of Ar₆ can optionally be bondedto one, two, three, or four ring substituents, so as to form asubstituted aryl or substituted heteroaryl ring, as those terms aredefined elsewhere herein.

The optional substituent residues or radicals bonded to Ar₆ can beselected from inorganic or organic radicals, as those terms are definedelsewhere herein. Although not wishing to be bound by theory, theheterocyclic amide compounds of the invention, including the Ar₆ radicaltogether with any additional substituent radicals are selected so thatthe Ar₆ radical has a geometry, size, and polarity that is suitable toallow the compounds of the invention to interact with and substantiallyfill, yet fit within, the binding regions of the target biologicalmolecules, so as to contribute to the effective binding of the compoundsto the binding sites in the biological target molecules. Therefore, insome embodiments, the Ar₆ aryl or heteroaryl radical, together anyadditional substituent radicals for comprises from 2 to 18 carbon atoms,or from 3 to 12 carbon atoms, or from 4 to 10 carbon atoms, or from 5 to8 carbon atoms.

In many embodiments, Ar₆ is a substituted or unsubstituted six memberedaromatic or heteroaromatic radical, such as a benzene, pyridine,pyrimidine, or pyrazine ring radical. In such embodiments, any relativeorientation of the bonds to Ar₅ and to the carbon atom that bridges tothe HAr heterocycles (i.e. ortho, meta, or para) can be employed.Nevertheless, in some embodiments, a “meta” orientation of the bonds toAr₅ and to the carbon atom that bridges to the HAr heterocycles canprovide superior biological activity. Such “meta” Ar₆ rings can haveadditional substituents, as discussed above. In some such embodimentsAr₆ has the Formula (215a), (215b), (215c) or (215d):

wherein R₁₂₅, R₁₂₆, R₁₂₇ and R₁₂₈ can be independently selected frominorganic substituents which include but are not limited to hydrogen,halogen, nitro, hydroxyl, or amino, or organic residues or radicals,examples of which include but are not limited to an alkyl, substitutedalkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cyano, acyloxy, mono-substituted amino, di-substituted amino,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, heteroaryl, alkoxy, haloalkoxy, substituted alkoxy,haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide orsubstituted dialkylcarboxamide residue.

In some compounds of the invention comprising Ar₆ rings of formulas(215a-d), R₁₂₅ is not hydrogen. Although the biochemical basis for theeffect may not necessarily be well understood, it believed that thepresence of a non-hydrogen R₁₂₅ substituent can significantly andunexpectedly improve the activity of the compounds as agents, formodulating lipid or carbohydrate metabolism, and/or producinganti-diabetic and/or anti-cholesteric activity. In some embodiments,preferred R₁₂₅, residues are an alkyl, substituted alkyl, haloalkyl,alkoxy, substituted alkoxy, haloalkoxy, halogen, amino, mono-substitutedamino, or disubstituted amino residue, particularly those comprisingfrom 1 to 6 carbons, or 1 to four carbons. Unexpectedly good biologicalactivity can often be obtained if R₁₂₅ is a small organic radical suchas a methoxy, triflouromethoxy, dimethylamino, or chloride radical, soas to yield an Ar₆ radical comprising Formulas (217a), (217b), (217c) or(217d):

wherein R₁₂₆, R₁₂₇ and R₁₂₈ are independently or together hydrogen orhalogen.

The compounds of the invention have a carbon atom bonded to both the Ar₆radical and the HAr heterocyclic radical, so as to bridge or link theAr₆ radical and the HAr heterocyclic radical. The bridging carbon atombears an R₁₀₉ substituent that can be selected from hydrogen, hydroxy,or an organic residue comprising 1 to 10 carbon atoms. In someembodiments R₁₀₉ is selected from hydrogen, an alkyl, a substitutedalkyl, hydroxy, an alkoxy or a haloalkoxy radical. In many embodiments,R₁₀₉ is hydrogen.

In some embodiments ----- represents a bond present and the compound isa benzylidene compound having Formula (220):

When ----- is present both E and Z configurations of the carbon-carbonbond between the benzylidene carbon and the HAr heterocycle are withinthe scope of the invention. Either isomer can predominate or be presentin pure form, or in a mixture, which may or may not have equalproportions of the E and Z isomers. For example, 2,4-thiazolidinedioneand 2-thioxo-4-thiazolidinedione of Formula (200) can have the followingstructures respectively:

When only one of the two isomer is shown in this specification or in theclaims, it should be presumed that both isomers and mixtures thereof areintended unless the context makes it plain that only a single isomer isintended.

In some embodiments ----- represents a bond absent and the compound is abenzyl compound with a single carbon-carbon bond between a benzyliccarbon and the HAr ring, the compounds having the Formula (222):

As already noted above, the 5 membered heterocyclic ring radicalcomprising the W, X, Y, and Z groups form one of four heterocycles,selected from a 2,4-thiazolidinedione, 2-thioxo-thiazolidine-4-one,2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one residue, whichcan be collectively termed “HAr” heterocycles. The four possible HArheterocyclic residues are shown in the drawing below:

All four of the HAr heterocycles shown above comprise at least one ringnitrogen atom bonded to a hydrogen atom. The nitrogen-bound hydrogenatoms of all four of the HAr heterocycles are known to be sufficientlyacidic so as to react with common laboratory bases such as organic aminecompounds, hydroxide salts, and the like.

The acidity of the four HAr heterocycles provides a ready method forpreparing salts of the compounds of the invention, by reaction with anappropriate base, so as to generate an anion from the compound of theinvention and a cation derived from the base employed. The salts formedby such reactions have the structure:

A wide variety of bases could be employed to produce such salts,including monovalent alkali metal hydroxides, divalent alkaline earthmetal hydroxides, or bases comprising trivalent metal salts such asaluminum. Alternatively, organic bases such as primary, secondary, ortertiary amines can react with the acidic hydrogens of the compounds ofthe invention to form ammonium salts. The base and/or its associatedcation are chosen so as to provide desirable solubility, toxicity,and/or bioavailability characteristics in the salt after formation ofthe desired salts. The identity of the base and/or the resulting cationwill of course vary somewhat with the identity of the compound of theinvention, and the nature of the pharmaceutical composition to beemployed and its physical form as a solid or liquid, and the nature ofany solvents and/or carriers employed.

Nevertheless, the United States Food and Drug Administration haspublished a list of pharmaceutically acceptable cations forpharmaceutically acceptable salts that includes aluminum, calcium,lithium, magnesium, potassium, sodium, and zinc cations, ammoniumcations formed by the reactions of acidic compounds with benzathine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine,procaine, t-butylamine, and tris(hydroxymethyl)aminomethane (“Tris”).Such “pharmaceutically acceptable” salts are often employed and/orevaluated for use in the invention simply because of the likelihood ofdecreased FDA regulatory scrutiny. Example 25 provides an example of thesynthesis of a particularly useful “Tris” salt of one of the compoundsof the invention.

Also, one or more compounds disclosed herein can include zwitterionicsalts formed by reaction of a nitrogen contained internally within thecompound, such as an amine, aniline, substituted aniline, pyridyl andlike residues with the acidic hydrogen of the HAr group. Alternatively,a basic nitrogen contained internally within the compound can be reactedwith an external acid, such as HCl, sulfuric acid, a carboxylic acid orthe like.

Compounds disclosed herein can exist in various tautomeric forms. Forexample, 2,4-thiazolidinedione-containing compounds disclosed herein canexist in the form of tautomers (224a), (224b) and (224c).

It is understood by those of skill in the art that tautomers can alsoexist with compounds of the invention that contain the heterocycle2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or2-thioxo-imidazolidine-4-one. For convenience, all of the tautomers canbe presented herein by a single formula, but it is understood that alltautomers are within the scope of the invention.

Selected compounds of the invention can also be described more narrowlythan the broadest embodiments described above. Two examples of suchnarrower descriptions are set forth below, but the meanings of thevarious relevant terms and symbols are intended the same as those sameterms and symbols in the description above.

In one narrower description of the invention, the invention relates to acompound having the structure:

wherein

-   -   a) the residue    -    has the structure:    -    wherein R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, or R₁₀₆, R₁₁₀, R₁₁₁ and        R₁₁₂ are independently selected from hydrogen, hydroxyl, a        halogen, amino, or an organic residue comprising 1 to 6 carbon        atoms;    -   b) Ar₆ has the structure:    -    wherein R₁₂₅ is halogen, or an organic substituent residue        comprising 1 to 4 carbon atoms selected from alkyl, haloalkyl;        cyano, amino, mono-substituted amino, di-substituted amino,        alkoxy, or haloalkoxy; and R₁₂₆, R₁₂₇, and R₁₂₈ are        independently selected from hydrogen, halogen, amino, and/or        organic substituents comprising 1 to 4 carbon atoms selected        from alkyl, halo alkyl, cyano, acyloxy, mono-substituted amino,        di-substituted amino, alkoxy, or haloalkoxy;    -   c) ----- is either present or absent; and    -   d) W, X, Y and Z together form a heterocyclic radical having the        structure:

or a pharmaceutically acceptable salt thereof.

In another yet narrower description of the invention, the inventionrelates to a compound having the structure:

wherein

-   -   a) the residue    -    has the structure:    -    wherein R₁₀₁, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆ and R₁₁₀ are independently        selected from hydrogen, or an alkyl comprising 1 to 4 carbon        atoms.    -   b) Ar₆ has the structure:    -    wherein R₁₂₆, R₁₂₇ and R₁₂₈ are independently selected from        hydrogen or a halogen; and    -   c) W, X, Y and Z together form a heterocyclic radical having the        structure:

or a pharmaceutically acceptable salt thereof.

The present invention also provides, but is not limited to, the specificspecies compounds set forth in the Examples, or a pharmaceuticallyacceptable salt thereof:

Making Compounds of the Invention

Various synthetic methods can be employed in the making of the compoundsdisclosed herein. A representative set of synthetic pathways is shown inFIG. 8 for the synthesis of precursors of the Ar₅ radical and theattached non-aromatic heterocyclic ring comprising an amide group. Thesynthetic precursors whose synthesis is shown in FIG. 8 that can becoupled with Ar₆ and subsequently elaborated to provide the compounds ofthe invention by the methods illustrated in FIG. 9.

One method of synthesizing precursors of the Ar₅ radical is shown inFIG. 8, and begins with anilines of structure (230), many of which arecommercially available from suppliers such as Aldrich Chemical Companyof Milwaukee Wis. Compounds of structure (230) can be coupled with anappropriately substituted acid chloride derivative of acrylic acid togive amide (232). The groups R₁₀₃, R₁₀₅, and R₁₀₆ can be introduced intocompounds of the invention by the selection of the appropriatelysubstituted acrylic acid chloride. Such acrylic acid chlorides areavailable by a variety of known methods, including as products of Wittigreactions of appropriate aldehydes and ketones with phosphorus ylids ofhaloacetic acid derivatives. Amide (232) can also be prepared by methodsknown in the art utilizing a carboxylic acid and a coupling agent suchas, for example, a carbodiimide. The amide (232) is converted to2-oxo-1,2,3,4-tetrahydroquinoline (234) through a Lewis Acidcyclization. One Lewis acid that can be utilized in the process is, forexample, AlCl₃. Mineral acids my effect the same cyclization. At thisstage R₁₀₁ can be introduced to give 2-oxo-1,2,3,4-tetrahydro-quinoline(236) by allowing R₁₀₁-LG, wherein LG is a leaving group, such as, forexample, Cl, Br, I, OTf, and the like, to react with the nitrogen anionof 2-oxo-1,2,3,4-tetrahydro-quinoline (234). The anion of2-oxo-1,2,3,4-tetrahydro-quinoline (234) can be generated using a basesuch as, for example, KOH/DMSO, NaH and the like.

Another method, for example, includes the use of aniline (237) that canbe coupled with an acid chloride to give amide (238). The groups R₁₀₃and R₁₀₄ can be introduced into compounds of the invention by theselection of the appropriate acid chloride. Amide (238) can also beprepared by methods known in the art utilizing a carboxylic acid and acoupling agent such as, for example, a carbodiimide. At this stage R₁₀₁can be introduced to give amide (240) by allowing R₁₀₁-LG to react withthe nitrogen anion of amide (238), wherein LG is a leaving group, suchas, for example, Cl, Br, I, OTf, and the like.2-oxo-2,3-dihydro-1H-indole (242) can be prepared from amide (240)through a Pd-assisted cyclization. Various ligands with Pd can beemployed, such as, for example, tricyclohexyl-phosphine. The methoxygroup of amide (242) can be converted to phenol (244) using a variety ofmethods known in the art, such as, for example, BBr₃. The resultingphenol (244) can be converted into triflate (246), or the like, usingtriflic anhydride or similar reagent that is suitable for coupling withAr₆.

Another method, for example, includes the use of readily availablephenylene diamines of structure (248), that can be condensed with oxylylchloride to give quinoxaline-2,3-dione (250). R₁₀₁ can be introduced byallowing R₁₀₁-LG to react with the nitrogen anion ofquinoxaline-2,3-dione (250), wherein LG is a leaving group, such as, forexample, Cl, Br, I, OTf, and the like. R₁₀₂ can be introduced byallowing R₁₀₂-LG to react with the nitrogen anion ofquinoxaline-2,3-dione (250), wherein LG is a leaving group, such as, forexample, Cl, Br, I, OTf, and the like. R₁₀₁ and R₁₀₂ can be the same ordifferent. Quinoxaline-2,3-dione (252) can be brominated to givequinoxaline-2,3-dione (254) using methods known in the art, such as, forexample, Br₂ or equivalent, in an appropriate solvent, such as aceticacid. Bromination might also be carried out prior to the introduction ofR₁₀₁ and R₁₀₂.

Various synthetic methods can be employed in coupling Ar₅ and Ar₆. Arepresentative set of synthetic pathways is shown in FIG. 9. One method,for example, includes coupling a boronic acid of Formula (262), R₁₄₀=H,with a suitable carbonyl-containing aryl of Formula (264), such asR₁₅₀=Br, I, Cl, triflate or the like, to give biaryl (266) that issubstituted with a carbonyl group, such as a formyl group (i.e.,R₁₀₉=H). Alternatively, boronic acid (262) can be coupled with aryl(268), such as when R₁₅₀=Br, I, Cl, triflate or the like, to give biaryl(270) that is subsequently formylated using techniques known in the art,such as the Vilsmeier or the Vilsmeier-Haack reaction, the Gattermanreaction, the Duff reaction, the Reimer-Tiemann reaction or a likereaction. Coupling reactions such as that described for the formation ofBiary) (266) and (270) can also be conducted using boronic esters, suchas where R₁₄₀ together with the boron from a pinacol borate ester(formation of pinacol esters: Ishiyama, T., et al., J. Org. Chem. 1995,60, 7508-7510, Ishiyama, T., et al., Tetrahedron Letters 1997, 38,3447-3450; coupling pinacol esters: Firooznia, F. et al., TetrahedronLetters 1999, 40, 213-216, Manickam, G. et al., Synthesis 2000, 442-446;all four citations incorporated herein by reference). In the example foraryl (268) when R₁₅₀ is a triflate, it can easily be obtained by knownmethods from the corresponding phenol.

Biaryl (270) can also be acylated, for example by the Friedel-CraftsAcylation reaction (using an acid chloride) or the like to give biaryl(266) where R₁₀₉ is not hydrogen. Alternatively, in a two step manner,biaryl (270) is formylated by first performing a halogenation step togive biaryl (272), such as a bromination, followed by a halogen-metalexchange reaction using an alkyl lithium or lithium tributylmagnesatecomplex as described by lida, et. al. in Tetrahedron Letters 2001, 42,4841-4844 and reaction with DMF or equivalent known in the art to givebiaryl (266) where R₁₀₉ is H. The carbonyl group of biaryl (266) cansubsequently be condensed with a heterocycle possessing an activemethylene moiety, such as 2,4-thiazolidinedione,2-thioxo-thiazohdine-4-one, 2,4-imidazolidinedione or2-thioxo-imidazolidine-4-one to give benzylidene (274). The carbonylgroup of biaryl (266) can also be reduced, such as with sodiumborohydride, diisobutyl aluminum hydride, or the like, to give benzylalcohol (276, R₁₆₀=OH) and converted to benzyl bromide (278, R₁₆₀=Br)with HBr or some other method known in the art, such as PPh₃/CBr₄ orconverted to another leaving group, such as, for example, mesylate oriodide. Benzyl bromide (278, R₁₆₀=Br) or like compound is allowed toreact with the anion(s) of 2,4-thiazolidinedione to give biaryl [(280),where: W=—C(O)—, X=—NH—, Y=—C(O)— and Z=—S—]. Similarly, anions of otherheterocycles disclosed herein can be used. Alternative, biaryl [(280),where: W=—C(O)—, X=—NH—, Y=—C(O)— and Z=—S—] can be prepared by areduction of benzylidene [(274), where: W=—C(O)—, X=—NH—, Y=—C(O)— andZ=—S—] using methods known in the art, such as hydrogenation in thepresence of Pd/C, Mg/MeOH, LiBH₄ in THF/pyridine and the like. A numberof methods suitable for reducing benzylidene compounds to benzylcompounds (including hydrogenation, reaction with metal hydridereagents, or dissolving metal reductions) are known to those of skill inthe art, and those methods can be applied in the methods of the instantinvention.

In an alternative manner, the coupling can take place between aryl(282), such as where R₁₅₀=Br, I, Cl, triflate or the like, and boronicacid (284, R₁₄₀=H or alkyl) to give the above mention biaryl (266). Alsoaryl (282) can be coupled with boronic acid (286) to give biaryl (270).Employing the same strategy as described above biaryl (270) can beconverted to biaryl (266).

Coupling of two aryl rings can be conducted using an aryl boronic acidor esters with an aryl halide (such as, iodo, bromo, or chloro),triflate or diazonium tetrafluoroborate; as described respectively inSuzuki, Pure & Applied Chem., 66:213-222 (1994), Miyaura and Suzuki,Chem. Rev. 95:2457-2483 (1995), Watanabe, Miyaura and Suzuki, Synlett.207-210 (1992), Littke and Fu, Angew. Chem. Int. Ed., 37:3387-3388(1998), Indolese, Tetrahedron Letters, 38:3513-3516 (1997), Firooznia,et. al., Tetrahedron Letters 40:213-216 (1999), and Darses, et. al.,Bull. Soc. Chim. Fr. 133:1095-1102 (1996); all incorporated herein byreference. According to this coupling reaction, precursors such as (262)and (264) can be employed:

where R₁₄₀ is either alkyl, cycloalkyl (i.e., pinacol) or hydrogen andR₁₅₀ is a halide (such as, iodo, bromo, or chloro), triflate ordiazonium tetrafluoroborate. Alternately, it is understood that thecoupling groups can be reversed, such as the use of (282) and (284), toachieve the same coupling product:

where R₁₄₀ and R₁₅₀ have the same meaning as described above. Thepreparation of the above mentioned precursors can be prepared by methodsreadily available to those skilled in the art. For example, the boronicester can be prepared from aryl (282, where R₁₅₀=halide) by conversionof the halide to the corresponding aryl lithium, followed by treatmentwith a trialkyl borate. Methods are know in the art to prepare pinacolboronic esters from triflates such as aryl (282, where R₁₅₀=triflate).The coupling reaction can also be conducted between an arylzinc halideand an aryl halide or triflate. Alternately, the coupling reaction canalso be executed using an aryl trialkyltin derivative and an aryl halideor triflate. These coupling methods are reviewed by Stanforth,Tetrahedron 54:263-303 (1998) and incorporated herein by reference. Ingeneral, the utilization of a specific coupling procedure is selectedwith respect to available precursors, chemoselectivity, regioselectivityand steric considerations.

Condensation of the biaryl carbonyl containing derivatives (e.g., FIG.9, compound (266)) with a suitable active methylene compound, such as,2,4-thiazolidinedione, can be accomplished by the use of methods knownin the art. For example, the biaryl carbonyl product from the couplingreaction can be condensed with an active methylene compound to give abenzylidene compound of Formula (200) (i.e., ----- is a bond) asdescribed by Tietze and Beifuss, Comprehensive Organic Synthesis(Pergamon Press), 2:341-394, (1991), incorporated herein by reference.It is understood by those skilled in the art that intermediates havinghydroxyl groups bonded thereto can be formed during condensation of abiaryl carbonyl containing derivative and an active methylene compound,as shown below.

The hydroxyl groups of intermediates (267) are often eliminated (aswater) during the condensation reaction, to form the desired benzylidenecompound. Nevertheless, the conditions of the reaction can be modifiedfor the isolation or further use of hydroxyl containing intermediates,and such embodiments are within the scope of the invention. Effectivecatalysts for the condensation can be selected from ammonia, primary,secondary and tertiary amines, either as the free base or the amine saltwith an organic acid, such as acetic acid. Examples of catalysts includepyrrolidine, piperidine, pyridine, diethylamine and the acetate saltsthereof. Inorganic catalysts can also be used for the condensation.Inorganic catalysts include, but are not limited to, titaniumtetrachloride and a tertiary base, such as pyridine; and magnesium oxideor zinc oxide in an inert solvent system. This type of condensation canbe strongly solvent-dependent and it is understood that routineexperimentation may be necessary to identify the optimal solvent with aparticular catalyst, preferable solvents include ethanol,tetrahydrofuran, dioxane or toluene; or mixtures thereof.

In view of the teachings and disclosure above, in some aspects, theinvention relates to methods for preparing the compounds of theinvention, wherein the method comprises

-   -   a) coupling        -   i) an Ar₅ precursor compound having the structure:        -   ii) with an Ar₆ precursor compound having the structure:        -   iii) to form a carbonyl containing precursor compound having            the structure:    -   b) further reacting the carbonyl containing precursor compound        so as to connect to the carbonyl of the carbonyl containing        precursor an HAr heterocycle.

The methods of making the compounds of the invention further comprisesteps wherein the further reacting comprises condensing the carbonylcontaining precursor compound with a compound having the structure

As is understood by those of ordinary skill in the art of syntheticorganic chemistry, the various synthetic strategies, organic reactions,and/or functional group transformations utilized herein can be performedby a number of strategies, reactions, or procedures other than thoseexplicitly described above. References for other synthetic proceduresthat can be utilized for the synthetic steps leading to the compoundsdisclosed herein can be found in, for example, March, J., AdvancedOrganic Chemistry, 4^(th) Edition, Weiley-Interscience (1992); orLarock, R. C., Comprehensive Organic Transformations, A Guide toFunctional Group Preparations, VCH Publishers, Inc. (1989), bothincorporated herein by reference.

Pharmaceutical Compositions

Although the compounds described herein can be administered as purechemicals, it is preferable to present the active ingredient as apharmaceutical composition. Thus another embodiment is the use of apharmaceutical composition comprising one or more compounds and/or apharmaceutically acceptable salt thereof, together with one or morepharmaceutically acceptable carriers thereof and, optionally, othertherapeutic and/or prophylactic ingredients. The carrier(s) must be‘acceptable’ in the sense of being compatible with the other ingredientsof the composition and not overly deleterious to the recipient thereof.

Pharmaceutical compositions include those suitable for oral, enteral,parental (including intramuscular, subcutaneous and intravenous),topical, nasal, vaginal, ophthalinical, sublingually or by inhalationadministration. The compositions can, where appropriate, be convenientlypresented in discrete unit dosage forms and can be prepared by any ofthe methods well known in the art of pharmacy. Such methods include thestep of bringing into association the active compound with liquidcarriers, solid matrices, semi-solid carriers, finely divided solidcarriers or combination thereof, and then, if necessary, shaping theproduct into the desired delivery system.

Pharmaceutical compositions suitable for oral administration can bepresented as discrete unit dosage forms such as hard or soft gelatincapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient; as a powder or as granules; as a solution, asuspension or as an emulsion. The active ingredient can also bepresented as a bolus, electuary or paste. Tablets and capsules for oraladministration can contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, or wetting agents. Thetablets can be coated according to methods well known in the art., e.g.,with enteric coatings.

Oral liquid preparations can be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can contain conventionaladditives such as suspending agents, emulsifying agents, non-aqueousvehicles (which can include edible oils), or one or more preservative.

The compounds can also be formulated for parenteral administration(e.g., by injection, for example, bolus injection or continuousinfusion) and can be presented in unit dose form in ampules, pre-filledsyringes, small bolus infusion containers or in multi-does containerswith an added preservative. The compositions can take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, andcan contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredient can be in powderform, obtained by aseptic isolation of sterile solid or bylyophilization from solution, for constitution with a suitable vehicle,e.g., sterile, pyrogen-free water, before use.

For topical administration to the epidermis, the compounds can beformulated as ointments, creams or lotions, or as the active ingredientof a transdermal patch. Suitable transdermal delivery systems aredisclosed, for example, in Fisher et al. (U.S. Pat. No. 4,788,603,incorporated herein by reference) or Bawas et al. (U.S. Pat. Nos.4,931,279, 4,668,504, and 4,713,224; all incorporated herein byreference). Ointments and creams can, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agents. Lotions can be formulated with an aqueous or oily baseand will in general also contain one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. The active ingredient can also be deliveredvia iontophoresis, e.g., as disclosed in U.S. Pat. Nos. 4,140,122,4,383,529, or 4,051,842; incorporated herein by reference.

Compositions suitable for topical administration in the mouth includeunit dosage forms such as lozenges comprising active ingredient in aflavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; mucoadherent gels, and mouthwashescomprising the active ingredient in a suitable liquid carrier.

When desired, the above-described compositions can be adapted to providesustained release of the active ingredient employed, e.g., bycombination thereof with certain hydrophilic polymer matrices, e.g.,comprising natural gels, synthetic polymer gels or mixtures thereof. Thepharmaceutical compositions according to the invention can also containother adjuvants such as flavorings, coloring, antimicrobial agents, orpreservatives.

Therefore, in some embodiments the invention relates to a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carriersand one or more compounds of the invention, or a pharmaceuticallyacceptable salt thereof, in an amount that can be used to effectivelytreat diabetes, cancer, or atherosclerosis, or modulate lipidmetabolism, carbohydrate metabolism, lipid and carbohydrate metabolism,or adipocyte differentiation, in a mammal.

Biological Activity Testing for Compounds of the Invention

The compounds of the present invention have been found to be potentcompounds in a number of biological assays, both in vitro and in vivo,that correlate to, or are representative of, human diseases.

For instance, many of the compounds of the invention can induce thedifferentiation of preadipocytes into adipocytes. This biologicalactivity (Harris and Kletzien, Mol. Pharmacol., 45:439-445 (1994);Wilson et al., J. Med. Chem. 39:665-668 (1996)) has been observed forcertain compounds that have antidiabetic activity in humans (Teboul etal., J. Biol. Chem. 270:28183-28187 (1995)) and has been used by many inthe art to screen new compounds for anti-diabetic activity. The abilityof the compounds to induce cells of the adipocyte lineage todifferentiate can also correlate to the ability of the compounds totreat or prevent other diseases including proliferative diseases such asbreast, prostate and other cancers.

The compounds of the invention have been screened in an in-vitroadipocyte differentiation assay, as described in Example 26. Mousepre-adipocyte 3T3-L1 cells were treated with compounds at concentrationsless than or equal to 10⁻⁶ M for 7 days. Pre-adipocyte cells that becomedifferentiated into adipocytes begin to accumulate lipids, andaccordingly can exhibit an increase in lipid content. Results from thetesting are shown in FIG. 1, wherein the lipid content of the cellsafter treatment with the compounds of the invention is displayed as afunction of the identity of the compound and the concentration at whichit was applied. The relative lipid content of the cells is plotted inFIG. 1 relative to the results obtained by the application of compound24, which has been shown to be a potent inducer of adipocytedifferentiation, and also a compound that is useful for the treatment ofdiabetes.

As can be seen from FIG. 1 and/or Example 26, several of the compoundswhose preparation is documented in the examples induced differentiationof the pre-adipocytes at concentrations ranging as low as 1×10⁻¹⁰ Molar,and hence showed a positive indication of biological activity sufficientto justify further in-vivo testing.

In order to demonstrate the activity of the various compounds of theinvention for effectiveness and/or activity for adipocytedifferentiation, the compound can be applied at a concentration of about1×10⁻⁶ M for a period of about 7 days, to mouse preadipocyte 3T3-L1cells, and measure the increase the lipid content of the cells. Thecompounds can be considered active for adipocyte differentiation if thelipid accumulation induced is at least about 20%, or at least about 40%of the lipid accumulation induced by5-[3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dionewhen it is applied to control cultures of mouse preadipocyte 3T3-L1cells at a concentration of about 1×10⁻⁷ M.

The ability of the compounds to function as antidiabetic agents can bedemonstrated in-vivo in certain known animal models for type 2 diabetes[Coleman, D. L, Diabetes, vol. 31, suppl 1, pp 1-6, (1982); Chang A. Y.et al, diabetes, pp 466-470, (1986)]. These known animal models includeamong others, db/db mice, ob/ob mice, and KKA^(y) mice.

Diabetes and Lipid Metabolism Efficacy Testing in KKA^(y) Mice (SeeResults in FIGS. 2 a-e and Example 27.)

Of the three mouse models, the KKA^(y) mice exhibit the most severesymptoms of type 2 diabetes, including hyperglycemia,hypertriglyceridemia and hypercholesterolemia, and therefore are oftenthe most difficult to treat.

As can be readily seen from FIGS. 2 a-2 e, the compounds of theinvention were found to be very effective for simultaneously andbeneficially decreasing serum glucose, serum triglyceride, and/or serumcholesterol in KKA^(y) Mice.

Diabetes and Lipid Metabolism Efficacy Testing in db/db Mutant Mice

(See Results in FIG. 3 and Example 28).

While both db/db mice, ob/ob mice are considered model of type 2diabetes, the severity of the disease in these models is less pronouncedthan in KKA^(y) mice. They are however still used as tools todemonstrate the efficacy of the compounds in treating type 2 diabetes.As can be readily seen from FIG. 3, Compound 25 was found to beeffective very for simultaneously and beneficially decreasing serumglucose and serum triglycerides in db/db Mice.

Activity for Inducing Cholesterol Efflux from Macrophage Foam Cells

(See Results in FIG. 4 and Example 29)

Elevated levels of cholesterol lead to atherosclerosis and heartdisease, which in many type 2 diabetes patients is the cause of death.Atherosclerotic lesions results from Cholesterol-loaded macrophage foamcells [Gown et al. (1986) Am. J. Phathol. 125, 191-207]. In vitro,macrophages that are cholesterol-loaded in cell culture can unloadexcess cholesterol, which can be measured in a “Cholesterol EffluxAssay” (see example 29). The cholesterol released from the MacrophageFoam Cells can be metabolized by the liver and eliminated from the body.Therefore, novel therapeutic agents that increase cholesterol effluxfrom macrophages in arteriosclerotic lesions can improve the outcome forpatients with coronary artery disease such as in obese and diabetespatients.

As can be readily seen from FIG. 4, Compound 2 was found to be veryeffective for inducing cholesterol efflux from Macrophage Foam Cells,this indicating its use for the control and/or treatment ofatherosclerosis.

Activity for Modulation of HDL and LDL Cholesterol Levels in DietInduced Hypercholesterolemic Sprague Dawley Rats

(See Results in FIG. 5 and Example 30.)

The ability of a compound to reduce certain lipids such as cholesterolor to change the ratio of good versus bad cholesterol, i.e. HDL versusLDL, can be measured in animal models. One animal model commonly usedfor such testing is the diet-induced hypercholesterolemic wild typeSprague Dawley rat (see example 30).

As can be readily seen from FIG. 5 a-c, Compounds 2, 6, and 25 werefound to provide unexpectedly beneficial modulation of HDL and LDLcholesterol levels in diet-induced hypercholeterolemic Sprague DawleyRats, thus indicating significant potential for the control and/ortreatment of atherosclerosis in diabetes patients.

Effect on Breast Cancer Tumor Progression Caucinogen Induced MammaryTumors in Wild Type Sprague Dawley Rats

(See Results in FIG. 6 and Example 31.)

The ability of the compounds to function as anti-breast cancer agentscan be demonstrated in vivo in carcinogen induced mammary tumors in wildtype Sprague Dawley Rats [Thompson H. J et al, Carcinogenesis, 13(9),1535-1539 (1992)].

As can be readily seen from FIG. 6, Compounds 6, 11, 13, and 25 wereunexpectedly found to slow or cause regression in the growth of breastcancer tumors in Sprague Dawley Rats, thus indicating significantpotential for the control and/or treatment of breast cancer in humans.

Comparison of Oral Bioavailability of Comparative Compound 24 andCompound 25.

(See Results in FIG. 7 and Example 32.)

Oral bioavailability is an important pharmaceutical characteristic for acompound to advance through drug development. A basic assessment of theoral bioavailability of a compound can be done in a single dosepharmacokinetic study in wild type rats.

As can be readily seen from FIG. 7, Compounds 25 exhibit unexpectedlysuperior bioavailability as compared to Compound 24.

Methods of Treating Diseases

Compounds disclosed herein are useful, for example, to modulatemetabolism (such as, for example, lipid metabolism and carbohydratemetabolism) or adipocyte differentiation. Changes in carbohydratemetabolism can directly or indirectly also result in changes of lipidmetabolism and, similarly, changes in lipid metabolism can lead tochanges in carbohydrate metabolism. An example is type 2 diabetes wherean increase in free fatty acids in the patients leads to decreasedcellular uptake and metabolism of glucose.

Carbohydrate metabolism can be up-regulated or down-regulated to eitherapproach the level of carbohydrate metabolism in a control or to deviatefrom the level of carbohydrate metabolism in a control. For example, thecompounds of the invention can be effective to lower serum glucoselevels of KKA^(y) or db/db mice maintained on a high fat diet by atleast about 5%, or at least about 10%, when orally administered to themice at a concentration of about 0.3 mg/kg for 7 days, as compared tocontrol mice that do not receive the compounds.

As a result of their activity for regulating carbohydrate metabolism,the compounds of the invention can be effective for treating type 2diabetes. Therefore, in some embodiments, the invention relates tomethods of treating type 2 diabetes comprising administering to a mammaldiagnosed as needing such treatment, including humans, one or morecompounds of the invention, or a pharmaceutically acceptable saltthereof, in an amount effective to treat type 2 diabetes. In someembodiments, the one or more compounds or salts are applied in an amounteffective to decrease blood glucose levels in the mammal by at leastabout 5%, or at least about 10%.

Modulation of lipid metabolism, for example, can include an increase oflipid content intracellularly or extracellularly. Modulation, forexample, could involve increase in lipid metabolism, such that lipidmetabolism is greater than that of a control. Modulation, also includes,for example, an increase in lipid metabolism, such that the lipidmetabolism approaches that of a control. For example, the compounds ofthe invention and their pharmaceutically acceptable salts can beemployed to induce cholesterol efflux from Macrophage Foam Cells asdescribed in Example 29, in order to treat atherosclerosis.

Modulation of lipid metabolism could also include a decrease of lipidcontent intracellularly or extracellularly. Modulation of metabolism canoccur directly for example, through binding of the compound of theinvention with its cognate receptor, which directly affects an increaseor decrease in lipid content by up-regulation or down-regulation of agene involved in lipid metabolism. Modulation of metabolism can alsooccur indirectly, for example, through binding of the compound of theinvention with its cognate receptor, which up-regulates ordown-regulates cellular differentiation or growth of cells that producelipids, thereby indirectly causing lipid metabolism to be modulated. Asshown in Examples 28 and 29, the compounds of the invention can beeffective to lower serum triglyceride levels of KKA^(y) or db/db micemaintained on a high fat diet by at least about 5%, or at least about10%, when orally administered to the mice at a concentration of about0.3 mg/kg for 7 days, as compared to control mice that do not receivethe compounds.

Therefore, in some embodiments, the invention relates to methods oftreating dyslipidemia comprising administering to a mammal diagnosed asneeding such treatment one or more compounds of the invention, or apharmaceutically acceptable salt thereof, in an amount effective todecrease triglyceride levels in the animal. In some such embodiments,the invention relates to such methods wherein the one or more compoundsor salts are applied in an amount effective to decrease triglyeridelevels by at least about 5%, or at least about 10%.

As is well known, cholesterol is a lipid that is closely linked withmany biochemical functions, but also with diseases such asatherosclerosis. As is illustrated in Examples 29 and 30, the compoundsof the invention can benefit modulate the level of cholesterol,including its manifestations in the HDL and LDL forms. Therefore, insome embodiments, the invention relates to a method of treatinghypercholesterolemia comprising administering to a mammal diagnosed asneeding such treatment one or more compounds the invention, or apharmaceutically acceptable salt thereof. In some embodiments, themethods apply the one or more compounds or salts in an amount effectiveto decrease serum cholesterol levels by at least about 5%, or at leastabout 10%., or to increase the concentration of HDL cholesterol, ordecrease the concentration of LDL cholesterol, or increase the HDL/LDLratio by at least about 5%, or at least about 10%.

It is understood that a variety of lipid molecules can be modulated. Thecompounds disclosed herein can modulate a single type of lipid molecule,such as a triglyceride, or the compounds disclosed herein can modulatemultiple types of lipid molecules. The compounds disclosed herein canalso modulate a single or variety of carbohydrate molecules.Unexpectedly, the compounds of the invention can simultaneously andbeneficially regulate carbohydrate and lipid metabolism so as tosimultaneously decrease levels of serum glucose, serum triglycerides,and serum cholesterol. Drugs having such a combination of beneficialproperties are of very high value for simultaneous treatment of type 2diabetes and/or its associated diseases, such as atherosclerosis.

The amide compounds of the invention are also useful for inducingadipocyte differentiation, which can produce a modulation of themetabolism of lipids, including triglycerides and cholesterol. As isshown in Example 26, the compounds of the invention can be effective,when applied at a concentration of about 1 uM for a period of about 7days, to induce differentiation of mouse preadipocyte 3T3-L1 cells so asto increase their lipid content by at least about 20%, or at least about40%, or at least about 50%. Such activity for adipocyte differentiationis well known to those of skill in the art to be associated withactivity for the treatment of diabetes, cancer, and/or inflammatorydiseases. Inflammatory responses of macrophage foam cells are known tobe involved in the formation atherosclerotic lesions. Without wishing tobe bound by theory, the compounds of the invention are believed to beinvolved in lessening such inflammatory responses, and/or inducing themacrophages to increase their release of cholesterol, so as to lessenthe buildup of cholesterol in blood vessel walls. Therefore, thecompounds of the invention are unexpectedly useful in treating diabetesand simultaneously treating the atherosclerosis, which often occurs indiabetic patients.

The compounds of the invention are also useful for treating diseases ofuncontrolled cellular proliferation, for which chronic inflammatoryresponses are known to be a factor, including various cancers. Thecomposition can be useful in the treatment of polycystic kidney diseaseand cancers such as, carcinomas, lymphomas, leukemias, and sarcomas. Arepresentative but non-limiting list of cancers is lymphoma, Hodgkin'sdisease, myeloid leukemia, bladder cancer, brain cancer, head and neckcancer, kidney cancer, lung cancers such as small cell lung cancer andnon-small cell lung cancer, myeloma, neuroblastoma/glioblastoma, ovariancancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer,melanoma, colon cancer, cervical carcinoma, breast cancer, andepithelial cancer. Compounds disclosed herein can also be used for thetreatment of inflammatory diseases such as osteoarthritis, rheumatoidarthritis, Crohn's Disease, pulmonary fibrosis, and Inflammatory BowelDisease.

Therefore, in some embodiments, the invention relates to method oftreating cancer comprising administering to a mammal diagnosed asneeding such treatment one or more compounds of the invention, or apharmaceutically acceptable salt thereof, in an amount effective totreat the cancer. In some embodiments the cancer treated is breastcancer.

The compounds of the invention have suitably low molecular weights andgood physiological stability. The compounds of the invention also haveexcellent oral bio-availability, as illustrated in Examples 27, 28, 30,31, and 32, and therefore, represent a class that have superiorpharmacological and physical properties that can be readily implementedto prevent, alleviate, and/or otherwise, treat disorders of lipid andcarbohydrate metabolism, such as obesity, dyslipidemia, type 2 diabetesand other diseases related to type 2 diabetes.

A preferred embodiment of the invention relates to the use of thecompounds disclosed herein. The compounds disclosed herein can be eitherused singularly or plurally, and in pharmaceutical compositions thereoffor the treatment of mammalian diseases, particularly those related tohumans. Compounds disclosed herein and compositions thereof can beadministered by various methods including, for example, orally,enterally, parentally, topically, nasally, vaginally, ophthalinically,sublingually or by inhalation for the treatment of diseases related tolipid metabolism, carbohydrate metabolism, lipid and carbohydratemetabolism such as polycystic ovary syndrome, syndrome X, type 2diabetes, including disorders related to type 2 diabetes such as,diabetic retinopathy, neuropathy, macrovascular disease ordifferentiation of adipocytes. Routes of administration and dose agesknown in the art can be found in Comprehensive Medicinal Chemistry,Volume 5, Hansch, C. Pergamon Press, 1990; incorporated herein byreference.

It will be further appreciated that the amount of the compound, or anactive salt or derivative thereof, required for use in treatment willvary not only with the particular salt selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will be ultimately at the discretion ofthe attendant physician or clinician.

In general, one of skill in the art understands how to extrapolate invivo data obtained in a model organism, such as an ob/ob or db/db mouse,to another mammal, such as a human. These extrapolations are not simplybased on the weights of the two organisms, but rather incorporatedifferences in metabolism, differences in pharmacological delivery, andadministrative routes. Based on these types of considerations, asuitable dose will, in alternative embodiments, typically be in therange of from about 0.5 to about 100 mg/kg/day, from about 1 to about 75mg/kg of body weight per day, from about 3 to about 50 mg per kilogrambody weight of the recipient per day.

The compound is conveniently administered in unit dosage form; forexample, in alternative embodiments, containing 0.5 to 1000 mg, 5 to 750mg, most conveniently, or 10 to 500 mg of active ingredient per unitdosage form.

One skilled in the art will recognize that dosage and dosage formsoutside these typical ranges can be tested and, where appropriate, beused in the methods of this invention.

In separate embodiments, the active ingredient can be administered toachieve peak plasma concentrations of the active compound of from about0.5 to about 75 μM, about 1 to 50 μM, or about 2 to about 30 μM. Thiscan be achieved, for example, by the intravenous injection of a 0.05 to5% solution of the active ingredient, optionally in saline, or orallyadministered as a bolus containing about 0.5-500 mg of the activeingredient. Desirable blood levels can be maintained by continuousinfusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusionscontaining about 0.4-15 mg/kg of the active ingredients.

The desired dose can conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself can befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as can be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

The following examples are given to illustrate the invention and are notintended to be inclusive in any manner:

EXAMPLES Example 15-[3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 1”

A mixture of toluene (80 mL), piperidine (380 μL), acetic acid (380 μL),3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde(7.5 g, 19.16 mmol) and 2,4-thiazolidinedione (2.25 g, 19.16 mmol) washeated at reflux overnight. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate and washed with water and brine,dried over MgSO₄. The residue was recrystallized successively fromethanol, dichloromethane/hexane and ethanol to afford 4.3 g (46%) of5-[3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4dione. mp 182-184° C. ¹H-NMR (300 MHz, DMSO-d-6): 1.27 (s, 6H), 2.08 (s,3H), 2.49 (s, 2H), 3.25 (s, 3H), 6.93 (s, 1H), 7.31 (s, 1H), 7.66 (s,1H), 7.67 (d, J=7.6 Hz, 1H), 7.75 (dd, J=7.6 and 1.7 Hz, 1H), 7.84 (s,1H), 12.71 (br s, 1H).

The intermediate3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehydewas prepared as follows:

a.3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde.

A mixture of 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (3.14 g,13.42 mmol), 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one(3.15 g, 11.19 mmol) and potassium carbonate (3.1 g, 22.38 mmol) intoluene (35 mL), ethanol (11.8 mL) and water (7.3 mL) was degassed withargon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.259 g,0.02 mmol) was added and the mixture heated at reflux under argonovernight. The solution was cooled to room temperature, diluted withethyl acetate and washed successively with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated. The residue waspurified on silica gel (20 to 30% ethyl acetate in hexane) to give 2.34g of3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde(54%). ¹H NMR (300 MHz; CDCl₃): 1.35 (s, 6H), 2.11 (s, 3H), 2.55 (s,2H), 3.35 (s, 3H), 6.79 (s, 1H), 7.20 (s, 1H), 7.54 (dd, J=3 and 8.4 Hz,1H), 7.85 (d, J=2.7 Hz, 1H), 7.90 (dd, J=2.1 and 8.7 Hz, 1H), 10.04 (s,1H).

b. 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid.

To a mixture of 2-(3-bromo-4-trifluoromethoxy-1-phenyl)-1,3-dioxolane(7.20 g, 22.9 mmol) in THF (70 mL) cooled to −78° C. under an atmosphereof argon was added n-BuLi (13.8 mL, 2.5 M, 34.4 mmol) dropwise. Theresulting suspension was stirred for 5 minutes and triisopropylborate(15.9 mL, 68.7 mmol) was added dropwise via syringe. The mixture wasstirred at −50° C. for 2 hours then warmed up to room temperature andstirred overnight at room temperature. 1.0 N HCl (50 mL) was slowlyadded to the reaction mixture. After 3 hours the mixture was dilutedwith ethyl acetate and the layers separated, the aqueous layer wasextracted once with ethyl acetate and the two organic layers combined.The resulting organic layer was washed with water, brine and dried(MgSO₄). The mixture was filtered, evaporated and the residue stirred inhexane. The resulting white suspension was filtered and the white soliddried under high vacuum to afford 3.00 g of3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (56%). ¹H NMR (300MHz; CDCl₃): δ 7.42 (d, J=7.0 Hz, 1H), 8.07 (dd, J₁=2.1 Hz, J₂=8.7 Hz,1H), 8.47 (d, J=1.8 Hz, 1H), 10.05 (s, 1H).

c. 2-(3-bromo-4-trifluoromethoxy-1-phenyl)-1,3-dioxolane.

To a solution of 3-bromo-4-trifluoromethoxybenzaldehyde (20 g, 74.0mmol) in toluene (200 mL) was added ethylene glycol (82.6 mL, 1.48 mol)and p-toluenesulfonic acid monohydrate (0.84 g, 4.44 mmol). The reactionmixture was heated at reflux overnight and the water was removed using aDean Stark apparatus. The solution was cooled to room temperature,poured into aqueous potassium carbonate (10%) and extracted with ethylacetate. The organic layer was washed with water, brine and dried(MgSO₄). The residue was purified on silica gel (eluent: 10% ethylacetate in hexane) to give 15.4 g of2-(3-bromo-4-trifluoromethoxy)-1,3-dioxolane (66%). ¹H NMR (500 MHz;CDCl₃): δ4.05 (m, 2H), 4.11 (m, 2H), 5.79 (s, 1H), 7.32 (d, 1H), 7.43(d, 1H), 7.77 (d, J=1.1 Hz, 1H).

d. 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one.

A mixture of powdered KOH (14.06 g, 0.250 mol) in DMSO (150 mL) wasstirred at 0° C. for 10 min.7-Bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (33.59 g, 0.125mol) was added cautiously, followed immediately by the addition ofmethyl iodide (39 mL, 0.625 mol). The reaction mixture was kept at 0° C.for 30 min then slowly warmed up to room temperature and stirredovernight at room temperature. The reaction mixture was poured intowater and extracted with dichloromethane washed with water and brine,dried (MgSO₄), filtered and evaporated to give 35.74 g of7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (99%) andused without further purification in the Suzuki coupling (step a). ¹HNMR (300 MHz; CDCl₃): 1.27 (s, 6H), 2.37 (s, 3H), 2.48 (s, 2H), 3.35 (s,3H), 7.12 (s, 1H), 7.16 (s, 1H).

e. 7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one.

To a solution of 3-methyl-but-2-enoic acid(3-bromo-4-methyl-phenyl)-amide (70.0 g, 261 mmol) at 90° C. was addedportion wise, under argon, with vigorous stirring aluminum chloride(52.3 g, 391 mmol) over 1.5 hr. The reaction mixture was stirred for 2hours at 110-120° C. The reaction mixture was cooled to room temperatureand ice-water was carefully added. The solution was extracted withdichloromethane and the organic washed with 2N HCl, water, saturatedaqueous NaHCO₃, water and brine, dried (MgSO₄), filtered and evaporated.The residue was crystallized from dichloromethane/hexane to give 46 g of7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one. The motherliquor was further chromatographed on silica gel (20% ethyl acetate inhexane) to give 6.2 g more of product. (75%). ¹H NMR (300 MHz; CDCl₃):1.30 (s, 6H), 2.33 (s, 3H), 2.46 (s, 2H), 7.07 (s, 1H), 7.10 (s, 1H),9.87 (br s, 1H).

f. 3-Methyl-but-2-enoic acid (3-bromo-4-methyl-phenyl)-amide.

To a biphasic mixture of 3-bromo-4-methylaniline (50 g, 0.269 mol), 10%NaOH (270 mL) and dichloromethane (160 mL) was added dropwise over aperiod of 2 hours 3,3-dimethylacryloyl chloride (36 mL, 0.322 mol) indichloromethane (95 mL). The solution was stirred at room temperaturefor 48 hours then diluted with water (100 mL). The aqueous layer wasfurther extracted with dichloromethane. The organic layers were combinedand washed with water and brine, dried (MgSO₄), filtered and evaporated.The white solid was triturated with hexane and collected to give 70 g(97%) of 3-Methyl-but-2-enoic acid (3-bromo-4-methyl-phenyl)-amide. ¹HNMR (300 MHz; CDCl₃): 1.89 (s, 3H), 2.21 (s, 3H), 2.33 (s, 3H), 5.68 (s,1H), 7.14 (d, J=8.0 Hz, 1H), 7.17 (br s, 1H), 7.33 (d, J=8.0 Hz, 1H),7.79 (s, 1H).

g. 3-bromo-4-methylaniline.

To a solution of 2-bromo-4-nitrotoluene (50 g, 0.231 mol in ethylacetate(330 mL) and Ethanol (150 mL) was added Tin(II)chloride dihydrate (208g, 0.924 mol) portionwise. The reaction mixture was stirred at roomtemperature overnight. The solution was then treated with potassiumcarbonate until pH=7 and filtered over celite. The filtrate was washedwith water, aqueous NaHCO₃, water and brine, dried (MgSO₄), filtered andevaporated to give 42.71 g (100%) of 3-bromo-4-methylaniline. ¹H NMR(300 MHz; CDCl₃): 2.27 (s, 3H), 3.57 (br s, 2H), 6.54 (dd, J=2.7 Hz and8.1 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H).

Example 25-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 2”

Prepared in a similar manner to example 1 using3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde.56% yield after column chromatography on silica gel (40% ethyl acetatein hexane). mp 156-154° C. ¹H-NMR (300 MHz, DMSO-d-6): 1.06 (t, J=7.5Hz, 3H); 1.26 (s, 6H>, 2.08 (s, 3H), 2.46 (s, 2H), 3.95 (br d, 2H), 6.97(s, 1H), 7.31 (s, 1H), 7.65 (s, 1H), 7.66 (dd, J=1.5 Hz and 9 Hz, 1H),7.75 (dd, J=2.4 Hz and 8.7 Hz, 1H), 7.87 (s, 1H), 12.71 (br s, 1H).

The intermediate3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehydewas prepared as follows:

a.3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde.

A mixture of 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (Example1b) (8.2 g, 34.84 mmol),7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (8.6 g,29.03 mmol) and potassium carbonate (8 g, 58.06 mmol) in toluene (80mL), ethanol (16 mL) and water (12 mL) was degassed with argon for 30minutes. Tetrakis(triphenylphosphine)palladium(0) (1.34 g, 0.04 mmol)was added and the mixture heated at reflux under argon for 48 hrs. Thesolution was cooled to room temperature, diluted with ethyl acetate andwashed successively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was purified on silica gel(30% ethyl acetate in hexane) to give 6.66 g of3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde(57%). ¹H NMR (300 MHz; CDCl₃): 1.20 (t, J=7.2 Hz, 3H), 1.33 (s, 6H),1.62 (s, 3H), 2.10 (s, 3H), 2.53 (s, 2H), 4.00 (br d, 2H), 6.81 (s, 1H),7.19 (s, 1H), 7.55 (dd, J=1.8 and 8.4 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H),7.97 (dd, J=2.1 and 8.4 Hz, 1H), 10.05 (s, 1H).

b. 7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one.

A mixture of powdered potassium hydroxide (3.35 g, 59.67 mmol) in DMSO(40 mL) was stirred at 0° C. for 10 min.7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (Example 1e) (8.0g, 29.83 mmol) was added cautiously, followed immediately by theaddition of ethyl iodide (12 mL, 149.17 mmol). The reaction mixture waskept at 0° C. for 30 min then slowly warmed up to room temperature andstirred overnight at room temperature. The reaction mixture was pouredinto water and extracted with dichloromethane washed with water andbrine, dried (MgSO₄), filtered and evaporated to give 8.8 g of7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one and usedwithout further purification in the Suzuki coupling (step a). ¹H NMR(300 MHz; CDCl₃): 1.24 (t, J=7.2 Hz, 1H), 1.25 (s, 6H), 2.37 (s, 3H),2.45 (s, 2H), 3.98 (q, 2H), 7.13 (s, 1H), 7.18 (s, 1H).

Example 35-[4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 3”

Prepared in a similar manner to example 1 using4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.73% yield after recrystallisation from ethanol. mp 258-260° C. ¹H NMR(300 MHz; DMSO) 1.25 (s, 3H); 1.27 (s, 3H), 2.07 (s, 3H), 2.47 (s, 2H),2.59 (s, 6H), 3.26 (s, 3H), 6.96 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.24 (s,1H), 7.28 (d, J=2.1 Hz, 1H), 7.49 (dd, J₁=2.1 Hz, J₂=8.7 Hz, 1H), 7.73(s, 1H), 12.44 (s, 1H).

The intermediate4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-benzaldehydewas prepared as followed:

a.4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.

A mixture of 6-dimethylamino-3-formyl-1-phenyl boronic acid (11.5 g,59.5 mmol), 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one(Example 1d) (14.0 g, 49.6 mmol) and potassium carbonate (13.7 g, 99.2mmol) in toluene (140 mL), ethanol (28 mL) and water (21 mL) wasdegassed with argon for 40 minutes.Tetrakis(triphenylphosphine)palladium(0) (3.5 g, 0.06 mmol) was addedand the mixture heated at reflux under argon for 24 hrs. The solutionwas cooled to room temperature, diluted with ethyl acetate and washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was purified on silica gel(30% ethyl acetate in hexane) to give 14.66 g of4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde(84%). ¹H NMR (300 MHz; CDCl₃): 1.31 (s, 3H), 1.33 (s, 3H), 2.10 (s,3H), 2.53 (s, 2H), 2.69 (s, 6H), 3.36 (s, 3H), 6.89 (s, 1H), 6.99 (d,J=8.7 Hz, 1H), 7.14 (s, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.77 (dd, J=2.4 Hzand 8.4 Hz, 1H), 9.82 (s, 1H).

b. 6-dimethylamino-3-formyl-1-phenyl boronic acid.

To a mixture of 2-(3-bromo-4-dimethylamino-1-phenyl)-1,3-dioxolane (8.8g, 32.34 mmol) in THF (80 mL) cooled to −78° C. under an atmosphere ofargon was added n-BuLi (19.4 mL, 2.5 M, 48.50 mmol) dropwise. Theresulting suspension was stirred for 5 minutes and triisopropylborate(22.4 mL, 97.0 mmol) was added dropwise via syringe. The mixture wasstirred at −50° C. for 2 hours then warmed up to room temperature andstirred overnight at room temperature. 1.0 N HCl (50 mL) was slowlyadded to the reaction mixture. After 4 hours 10% aqueous potassiumcarbonate was added to the reaction mixture until pH=6-7. The solutionwas diluted with ethyl acetate and the layers separated. The organiclayer was further washed with water, brine and dried (MgSO₄). Themixture was filtered and evaporated to afford 6.4 g of crude6-dimethylamino-3-formyl-1-phenyl boronic acid used without furtherpurification in the Suzuki coupling (step a).

c. 2-(3-bromo-4-dimethylamino-1-phenyl)-1,3-dioxolane.

To a solution of 3-bromo-4-dimethylamino-benzaldehyde (10 g, 43.84 mmol)in toluene (80 mL) was added ethylene glycol (48.9 mL, 877 mmol) andp-toluenesulfonic acid monohydrate (0.5 g, 2.63 mmol). The reactionmixture was heated at reflux overnight and the water was removed using aDean Stark apparatus. The solution was cooled to room temperature,aqueous potassium carbonate (10%) was added and the solution extractedwith ethyl acetate. The organic layer was washed with water, brine anddried (MgSO₄). The residue was purified on silica gel (eluent: 10% ethylacetate in hexane) to give 10.84 g of2-(3-bromo-4-dimethylamino-1-phenyl)-1,3-dioxolane. (90%). ¹H NMR (300MHz; CDCl₃): δ 2.81 (s, 6H), 4.02 (m, 2H), 4.13 (m, 2H), 5.74 (s, 1H),7.06 (d, J=8.1 Hz, 1H), 7.43 (dd, J=1.1 Hz and 8.4 Hz, 1H), 7.69 (d,J=1.5 Hz, 1H).

d. 3-bromo-4-dimethylamino-benzaldehyde.

To a solution of 4-dimethylamino-benzaldehyde (10 g, 67.03 mmol) indichloromethane (250 mL) was added pyridinium tribromide (21.4 g, 67.03mmol) and the reaction mixture stirred at room temperature overnight.The solution was washed with water and brine, dried (MgSO₄), filteredand evaporated. The residue was purified on silica gel (eluent: 15%ethyl acetate in hexane) to give 14.06 g of3-bromo-4-dimethylamino-benzaldehyde (92%). ¹H NMR (300 MHz; CDCl₃): δ2.59 (s, 6H), 7.06 (d, J=8.1 Hz, 1H), 7.75 (dd, J=7.8 Hz and 1.5 Hz,1H), 5.74 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 7.43 (dd, J=2.1 Hz and 8.4Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 9.81 (s, 1H).

Example 45-[4-Dimethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 4”

Prepared in a similar manner to example 1 using4-Dimethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.61% yield after recrystallisation from ethanol. mp 266-268° C. ¹H-NMR(300 MHz, DMSO-d-6): 1.09 (t, J=6.6 Hz, 3H), 1.27 (2 s, 6H), 2.08 (s,3H), 2.49 (d, 2H), 2.59 (s, 6H), 3.98 (m, 2H), 7.01 (s, 1H), 7.10 (d,J=8.7 Hz, 1H), 7.25 (s, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.50 (dd, J₁=7.7Hz, J₂=2.1 Hz, 1H), 7.74 (s, 1H), 7.84 (s, 1H), 12.44 (br s, 1H).

The intermediate4-Dimethylamino-3-(1-ethyl-4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehydewas prepared in a similar manner to example 3a using6-dimethylamino-3-formyl-1-phenyl boronic acid (example 3b) and7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example2b). 59% yield. ¹H NMR (300 MHz; CDCl₃): 1.21 (t, J=6.9 Hz, 3H), 1.32(s, 6H), 2.12 (s, 3H), 2.52 (s, 2H), 2.70 (s, 6H), 4.09 (m, 2H), 6.93(s, 1H), 6.98 (d, J=8.7 Hz, 1H), 7.16 (s, 1H), 7.59 (d, J=2.1 Hz, 1H),7.77 (dd, J=2.1 Hz and 8.4 Hz, 1H), 9.84 (s, 1H).

Example 55-[3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-chloro-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 5”

Prepared in a similar manner to example 1 using4-chloro-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.50% yield after recrystallisation from ethanol. mp 176-178° C. ¹H-NMR(300 MHz, DMSO-d-6): 1.25 (s, 3H), 1.28 (s, 3H), 2.07 (s, 3H), 2.50 (s,2H), 3.24 (s, 3H), 7.90 (s, 1H), 7.29 (s, 1H), 7.56 (s, 1H), 7.62 (d,J=8.7 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.83 (s, 1H), 12.68 (br s, 1H).

The intermediate4-chloro-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.was prepared as follows:

a.4-chloro-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.

A mixture of 6-chloro-3-formyl-1-phenyl boronic acid (1.18 g, 6.38mmol), 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one(Example 1d) (1.5 g, 5.32 mmol) and potassium carbonate (1.47 g, 10.64mmol) in toluene (15 mL), ethanol (3 mL) and water (2 mL) was degassedwith argon for 30 minutes. Pd (Ph₃)₄ (0.123 g, 0.02 mmol) was added andthe mixture heated at reflux under argon overnight. The solution wascooled to room temperature, diluted with ethyl acetate and washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was purified on silica gel(0 to 20% ethyl acetate in hexane) to give 0.514 g of4-chloro-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde(28%). ¹H NMR (300 MHz; CDCl₃): 1.33 (s, 3H), 1.36 (s, 3H), 2.09 (s,3H), 2.55 (2 s, 2H), 3.35 (s, 3H), 6.76 (s, 1H), 7.19 (s, 1H), 7.65 (d,J=8.1 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.97 (dd, J=2.1 and 8.4 Hz, 1H),10.02 (s, 1H).

b. 6-chloro-3-formyl-1-phenyl boronic acid.

Prepared in a similar manner to example 1b using2-(3-bromo-4-chloro-1-phenyl)-1,3-dioxolane e (70%). ¹H NMR (300 MHz;DMSO-d₆+1 drop of D₂O): δ 7.61 (d, J=8.4 Hz, 1H), 7.84 (dd, J₁=2.1 Hz,J₂=8.4 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 10.0 (s, 1H).

c. 2-(3-bromo-4-chloro-1-phenyl)-1,3-dioxolane.

Prepared in a similar manner to example 1c using3-bromo-4-chlorobenzaldehyde (90%). ¹H NMR (500 MHz; CDCl₃): δ 4.03 (m,2H), 4.09 (m, 2H), 5.79 (s, 1H), 7.35 (dd, J=2.1 Hz and 8.4 Hz, 1H),7.44 (d, J=8.1 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H).

d. 3-bromo-4-chlorobenzaldehyde.

To a solution of 4-chlorobenzaldehyde (20.5 g, 0.142 mol) intrifluoroacetic acid (83 mL) and sulfuric acid (16.6 mL) was addedN-bromosuccinimide (51.6 g, 0.288 mol) in portion over 6 hrs. Thereaction mixture was stirred at room temperature for 4 days. Thesolution was poured on ice-water and extracted with dichloromethane. Theorganic layer was washed with water, saturated aqueous NaHCO₃, water andbrine, dried (MgSO₄), filtered and evaporated. The residue was taken upin hexane, filtered and evaporated to give 20.4 g of crude3-bromo-4-chlobenzaldehyde that was used without purification in thenext step (5c). ¹H NMR (300 MHz; CDCl₃): 7.62 (d, J=8.1 Hz, 1H), 7.80(dd, J=2.1 and 8.4 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 9.94 (s, 1H).

Example 65-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-chloro-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 6”

Prepared in a similar manner to example 1 using4-chloro-3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.41% yield after recrystallisation from ethanol. mp 221-223° C. ¹H-NMR(300 MHz, DMSO-d-6): 1.07 (t, J=7.5 Hz, 3H), 1.26 (2 s, 6H), 2.05 (s,3H), 2.46 (s, 2H), 2.50 (m, 2H), 3.95 (br d, 2H), 6.94 (s, 1H), 7.03 (s,1H), 7.56 (d, J=2.1 Hz, 1H), 7.61 (dd, J=2.1 and 8.1 Hz, 1H), 7.75 (d,J=8.1 Hz, 1H), 7.84 (s, 1H), 12.68 (br s, 1H).

The intermediate4-chloro-3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-benzaldehydewas prepared in a similar manner as example 5a using7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example2b) and 6-chloro-3-formyl-1-phenyl boronic acid (example 5b). Yield:46%. ¹H NMR (300 MHz, CDCl₃): 1.21 (t, J=6.9 Hz), 1.32 (s, 3H), 1.34 (s,3H), 2.09 (s, 3H), 2.53 (2 s, 2H), 4.01 (m, 2H), 6.76 (s, 1H), 7.20 (s,1H), 7.65 (d, J=8.1 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.84 (dd, J=2.1 and8.4 Hz, 1H), 10.02 (s, 1H).

Example 75-[2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 7”

Prepared in a similar manner to example 1 using2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.64% yield. mp 271-276° C. ¹H-NMR (300 MHz, DMSO-d-6): 1.27 (s, 6H), 2.01(s, 3H), 2.48 (s, 2H), 3.22 (s, 3H), 3.82 (s, 3H), 6.90 (s, 1H), 7.20(d, J=8.8 Hz, 1H), 7.28 (s, 1H), 7.58 (t, J=8.8 Hz, 1H), 7.76 (s, 1H),12.66 (br s, 1H).

The intermediate2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehydewas prepared as follows:

a.2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-benzaldehyde.

To a solution of7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (example 1d)(0.96 g, 3.40 mmol) in dioxane (2 mL) were added under argon,triethylamine 1.9 mL, 13.61 mmol), palladium acetate (38 mg, 0.17 mmol),2-(dicyclohexylphosphino) biphenyl (238 mg, 0.68 mmol) and pinacolborane(1M in THF, 10.2 mL, 10.2 mmol). The mixture was stirred at 80° C. for 1hr 45 min, then cooled to room temperature. Water (1.5 mL), bariumhydroxide octahydrate (3.22 g, 10.20 mmol) and 2-Fluoro-3-iodo-4-methoxybenzaldehyde dissolved in dioxane (7 mL) were successively added and themixture heated at 100° C. for 13 hrs. The mixture was cooled to roomtemperature and filtered over celite. Brine was added and the aqueouslayer was extracted with dichloromethane. The organic extract was washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was purified on silica gel(20% to 30% ethyl acetate in hexane) to give 0.63 g of2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde(52%). ¹H NMR (300 MHz; CDCl₃): 1.33 (s, 3H), 1.35 (s, 3H), 2.09 (s,3H), 2.54 (s, 2H), 3.35 (s, 3H), 3.87 (s, 3H), 6.79 (s, 1H), 6.92 (d,J=8.7 Hz, 1H), 7.21 (s, 1H), 7.94 (t, J=8.7 Hz, 1H), 10.25 (s, 1H).

b. 2-Fluoro-3-iodo-4-methoxy benzaldehyde.

To a solution of 3-fluoroanisole (24 g, 190 mmol) in dichloromethane(350 mL) was added at room temperature pyridium tribromide (61 g, 190mmol). The reaction mixture was stirred at room temperature for 24 hrs,then washed successively with water and brine, dried (MgSO₄), filteredand evaporated. The residue was chromatographed on silica gel (10% ethylacetate in hexane) to give 34.5 g of 4-bromo-3-fluoro anisole (88%) useas this in the next step. ¹H NMR (300 MHz; CDCl₃): 3.79 (s, 3H), 6.62(d, J=10 Hz, 1H), 6.71 (d, J=10 Hz, 1H), 7.40 (t, J=9 Hz, 1H), 10.25 (s,1H).

To a solution of 4-bromo-3-fluoro anisole (34.4 g, 168 mmol) inanhydrous THF (300 mL) was added dropwise, at −78° C. under argon,n-BuLi (2.5 M in THF, 101 mL, 252 mol). After 5 min DMF (40 mL, 503mmol) was added and the reaction micture was kept at −78° C. for 2 hrs.Aqueous NH₄Cl (250 mL) was carefully added and the layers separated. Theaqueous phase was further extracted with ethyl acetate. The organicphases were combined and washed successively with water, brine and dried(MgSO₄). The residue was purified on silica get (eluent: 10% ethylacetate in hexane) to give 13.99 g of 2-fluoro-4-methoxy-benzaldehyde(54%). ¹H NMR (300 MHz; CDCl₃): 3.88 (s, 3H), 6.65 (d, J=12.3 Hz, 1H),6.80 (d, J=8.7 Hz, 1H), 7.82 (t, J=8.7 Hz, 1H), 10.21 (s, 1H).

To a solution of 2-fluoro-4-methoxy-benzaldehyde (13.98 g, 90.7 mmol) intoluene (100 mL) was added ethylene glycol (101 mL, 1.81 mol) andp-toluenesulfonic acid monohydrate (1.04 g, 5.44 mmol). The reactionmixture was heated at reflux for 16 hrs. The water was removed using aDean Starck apparatus. After cooling, aqueous potassium carbonate (10%,200 mL) was added and the mixture stirred for 30 minutes. The solutionwas extracted with ethyl acetate. The organic phase was washedsuccessively with 10% aqueous potassium carbonate, brine and dried(MgSO₄). The residue was purified on silica gel (eluent: 10% ethylacetate in hexane) to give 9.187 g of2-(2-fluoro-4-methoxy-phenyl)-[1,3] dioxolane (51%). ¹H NMR (300 MHz;CDCl₃): 3.81 (s, 3H), 4.06 (m, 2H), 4.15 (m, 2H), 6.03 (s, 1H), 6.60(dd, J=12.3 and 2.7 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 7.44 (t, J=8.4 Hz,1H).

To a solution of 2-(2-fluoro-4-methoxy-phenyl)-[1,3] dioxolane (4.27 g,21.54 mmol) in anhydrous THF (30 mL) was added, at −78° C. under argon,n-BuLi (1.6 M in hexane, 13.5, 21.54 mmol). The resulting orangesolution was stirred at −78° C. for 2 hours then iodine (6.015 g, 23.70mmol) in THF (30 mL) was added. At the end of the addition the reactionmixture was warmed to room temperature and stirred for 1 hr. Thesolution was extracted with ethyl acetate. The organic phase was washedsuccessively with 10% aqueous sodium thiosulfate (2×50 mL), water, brineand dried (MgSO₄), filtered and evaporated to give 5.794 g of crude2-(2-fluoro-3-iodo-4-methoxy-phenyl)-[1,3]dioxolane use as this in thenext step.

To a solution of 2-(2-fluoro-3-iodo-4-methoxy-phenyl)-[1,3] dioxolane(5.284 g, 16.30 mmol) in acetone (170 mL) was added HCl (1N, 170 mL) andthe solution stirred at room temperature for 48 hrs. The solution wasextracted with ethyl acetate and washed successively with water, brine,dried (MgSO₄), filtered and evaporated. The residue was purified onsilica gel (eluent: 10% ethyl acetate in hexane) to give 2.22 g of2-Fluoro-3-iodo-4-methoxy benzaldehyde (38% for 2 steps). ¹H NMR (300MHz; CDCl₃): 4.00 (s, 3H), 6.74 (d, J=8.4 Hz, 1H), 7.88 (t, J=8.1 Hz,1H), 10.21 (s, 1H).

Example 85-[3-(1-Propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 8”

Prepared in a similar manner to example 1 using3-(1-Porpyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde.45% yield after crystallization from ethyl acetate and hexane. mp219-2230C. ¹H-NMR (300 MHz, DMSO-d-6): 0.84 (t, J=7.2 Hz, 3H), 1.26 (s,6H), 1.49 (m, 2H), 2.07 (s, 3H), 2.46 (s, 2H), 3.95 (br d, 2H), 6.97 (s,1H), 7.31 (s, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.75(dd, J₁=2.4 Hz, J₂=8.7 Hz, 1H), 7.87 (s, 1H), 12.71 (br s, 1H). Theintermediate3-(1-propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehydewas prepared as follows:

a.3-(1-Propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde.

A mixture of 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (Example1b) (0.905 g, 3.87 mmol),7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (1.0 g,3.22 mmol) and potassium carbonate (0.89 g, 6.44 mmol) in toluene (10mL), ethanol (2 mL) and water (1.5 mL) was degassed with argon for 30minutes. Tetrakis(triphenylphosphine)palladium(0) (0.186 g, 0.161 mmol)was added and the mixture heated at reflux under argon for 24 hrs. Thesolution was cooled to room temperature, diluted with ethyl acetate andwashed successively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was purified on silica gel(0-15% ethyl acetate in hexane) to give 0.70 g of3-(1-propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde(52%). ¹H NMR (300 MHz; CDCl₃): 0.92 (t, J=7.2 Hz, 3H), 1.33 (s, 6H),1.61 (m, 5H), 2.09 (s, 3H), 2.53 (s, 2H), 3.95 (br d, 2H), 6.78 (s, 1H),7.19 (s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.98 (dd,J=2.1 and 8.74 Hz, 1H), 10.05 (s, 1H).

b. 7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one.

A mixture of powdered potassium hydroxide (1.26 g, 22.38 mmol) in DMSO(40 mL) was stirred at 0° C. for 10 min.7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (Example 1e) (3.0g, 11.19 mmol) was added cautiously, followed immediately by theaddition of 1-iodopropane (5.5 mL, 55.95 mmol). The reaction mixture waswarmed up to room temperature and stirred overnight at room temperature.The reaction mixture was poured into water and extracted withdichloromethane washed with water and brine, dried (MgSO₄), filtered andevaporated to give 4.0 g of7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one and usedwithout further purification in the Suzuki coupling (step a). ¹H NMR(300 MHz; CDCl₃): 0.98 (t, J=7.5 Hz, 1H), 1.26 (s, 6H), 1.65 (t, J=7.5Hz, 1H), 2.37 (s, 3H), 2.46 (s, 2H), 3.88 (t, J=7.8 Hz, 2H), 7.13 (s,1H), 7.15 (s, 1H).

Example 95-[4-Dimethylamino-3-(1-propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 9”

Prepared in a similar manner to example 1 using4-Dimethylamino-3-(1-propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.67% yield after recrystallisation from ethanol. mp 258-260° C. ¹H-NMR(300 MHz, DMSO-d-6): 0.86 (t, J=7.5 Hz, 3H), 1.24 (s, 3H), 1.26 (s, 3H),1.53 (m, 2H), 2.07 (s, 3H), 2.46 (2 s, 2H), 2.58 (s, 6H), 3.90 (br m,2H), 7.02 (s, 1H), 7.10 (d, J=9.0 Hz, 1H), 7.25 (s+d, 2H), 7.50 (dd,J₁=2.1 Hz, J₂=8.4 Hz, 1H), 7.74 (s, 1H), 12.44 (brs, 1H).

The intermediate4-Dimethylamino-3-(1-propyl-4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehydewas prepared in a similar manner to example 3a using6-dimethylamino-3-formyl-1-phenyl boronic acid (example 3b) and7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example8b). 57% yield. ¹H NMR (300 MHz; CDCl₃): 0.93 (t, J=7.2 Hz, 3H), 1.32 (2s, 6H), 1.64 (m, 5H), 2.12 (s, 3H), 2.68 (s, 6H), 3.91 (m, 2H), 6.89 (s,1H), 6.98 (d, J=8.1 Hz, 1H), 7.15 (s, 1H), 7.59 (d, J=2.1 Hz, 1H), 7.78(dd, J=2.1 Hz and 8.4 Hz, 1H), 9.83 (s, 1H).

Example 105-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-4-methoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 10”

Prepared in a similar manner to example 1 using2-Fluoro-4-methoxy-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.81% yield after recrystallisation from ethanol. mp 279-281° C. ¹H-NMR(300 MHz, DMSO-d-6): 1.05 (t, J=6.7 Hz, 3H), 1.25 (s, 6H), 2.01 (s, 3H),2.46 (s, 2H), 3.83 (s, 3H), 3.93 (q, J=6.7 Hz, 2H), 6.94 (s, 1H), 7.20(d, J=8.8 Hz, 1H), 7.28 (s, 1H), 7.58 (t, J=8.8 Hz, 1H), 7.77 (s, 1H),12.65 (br s, 1H).

The intermediate2-Fluoro-4-methoxy-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehydewas prepared in a similar manner to example 7a using7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example2b) and 2-Fluoro-3-iodo-4-methoxy benzaldehyde (example 7b). 59% yield.¹H NMR (300 MHz; CDCl₃): 1.21 (t, J=6.9 Hz, 3H), 1.31 (s, 3H), 1.34 (s,3H), 1.60 (s, 2H), 2.10 (s, 3H), 2.52 (s, 2H), 3.88 (s, 3H), 4.02 (q,J=7.2 Hz, 1H), 6.82 (s, 1H), 6.93 (d, J=9.0 Hz, 1H), 7.22 (s, 1H), 7.95(t, J=8.1 Hz, 1H), 10.26 (s, 1H).

Example 115-[3-(1-Isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as, “Compound 11”

Prepared in a similar manner to example 1 using3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde.48% yield after crystallization from ethanol/water. mp 233-235° C.¹H-NMR (300 MHz, DMSO-d-6): 1.26 (s, 6H), 1.38 (s, 3H), 1.40 (s, 3H),2.07 (s, 3H), 2.38 (s, 2H), 4.62 (m, 1H), 6.98 (s, 1H), 7.28 (s, 1H),7.66 (m, 2H), 7.76 (dd, J₁=1.8 Hz, J₂=8.7 Hz, 1H), 7.87 (s, 1H), 12.71(br s, 1H).

The intermediate3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehydewas prepared as follows:

a.3-(1-Isoropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde.

A mixture of 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (Example1b) (1.09 g, 4.64 mmol),7-bromo-1-isopropyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (1.2g, 3.87 mmol) and potassium carbonate (1.07 g, 7.74 mmol) in toluene (10mL), ethanol (2 mL) and water (1.5 mL) was degassed with argon for 30minutes. Tetrakis(triphenylphosphine)palladium(0) (0.224 g, 0.194 mmol)was added and the mixture heated at reflux under argon for 24 hrs. Thesolution was cooled to room temperature, diluted with ethyl acetate andwashed successively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was purified on silica gel(0-15% ethyl acetate in hexane) to give 0.54 g of3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde(33%). ¹H NMR (300 MHz; CDCl₃): 1.32 (s, 6H), 1.48 (s, 3H), 1.50 (s,3H), 2.09 (s, 3H), 2.45 (s, 2H), 4.7 (m, 1H), 6.91 (s, 1H), 7.16 (s,1H), 7.55 (d, J=8.4 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.98 (dd, J=1.8 and8.4 Hz, 1H), 10.05 (s, 1H).

b. 7-bromo-1-isopropyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one.

Prepared in a similar manner to example 1d using7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-7-yl)-2-one (example1e) and 2-iodopropane. 72% yield. ¹H NMR (300 MHz; CDCl₃): 1.25 (s, 1H),1.51 (s, 3H), 1.53 (s, 3H), 2.36 (s, 3H), 2.38 (s, 2H), 4.62 (m, 1H),7.10 (s, 1H), 7.27 (s, 1H).

Example 125-[4-Dimethylamino-3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 12”

Prepared in a similar manner to example 1 using4-Dimethylamino-3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.72% yield. mp 274-276° C. ¹H-NMR (300 MHz, DMSO-d-6): 1.24 (s, 3H), 1.26(s, 3H), 1.40 (m, 6H), 2.08 (s, 3H), 2.38 (d, 2H), 2.58 (s, 6H), 4.71(m, 1H), 7.02 (s, 1H), 7.12 (d, J=9 Hz, 1H), 7.22 (s, 1H), 7.28 (d,J=2.1 Hz, 1H), 7.50 (dd, J₁=1.8 Hz, J₂=8.7 Hz, 1H), 7.75 (s, 1H), 12.45(br s, 1H).

The intermediate4-Dimethylamino-3-(1-isopropyl-4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehydewas prepared in a similar manner to example 3a using6-dimethylamino-3-formyl-1-phenyl boronic acid (example 3b) and7-bromo-1-isoprpyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one(example 11b). 48% yield. ¹H NMR (300 MHz; CDCl₃): 1.31 (s, 6H), 1.48(s, 6H), 2.10 (s, 3H), 2.44 (s, 2H), 2.69 (s, 6H), 4.76 (m, 2H), 6.98(d, 1H), 7.02 (s, 1H), 7.12 (s, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.77 (dd,J=1.5 Hz and 8.7 Hz, 1H), 9.83 (s, 1H).

Example 135-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2,5-difluoro-4-methoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 13”

Prepared in a similar manner to example 1 using3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2,5-difluoro-4-methoxy-benzaldehyde.22% yield after recrystallisation from dichloromethane and hexane. mp203-207° C. ¹H NMR (300 MHz; DMSO) 1.05 (t, J=6.9 Hz, 3H), 1.25 (s, 6H),2.05 (s, 3H), 2.47 (s, 2H), 3.80 (s, 3H), 3.94 (m, 1H), 7.04 (s, 1H),7.31 (s, 1H), 7.47 (dd, J₁=6.9 Hz, J₂=12.3 Hz, 1H), 12.77 (s, 1H).

The intermediate3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2,5-difluoro-4-methoxy-benzaldehydewas prepared in a similar manner to example 7a using7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example2b) and 3-bromo-2,5-difluoro-4-methoxy benzaldehyde. 14% yield. ¹H NMR(300 MHz; CDCl₃): 1.21 (t, J=6.9 Hz, 3H), 1.32 (s, 3H), 1.33 (s, 3H),2.13 (s, 3H), 2.53 (s, 2H), 3.81 (2 s, 3H), 4.02 (q, J=6.9 Hz, 1H), 6.81(s, 1H), 7.23 (s, 1H), 7.68 (dd, J₁=6.3 Hz, J₂=11.7 Hz, 1H), 10.25 (2 s,1H).

a. 3-bromo-2,5-difluoro-4-methoxy benzaldehyde

Hexamethyltetramine (53.88 g, 0.384 mmol) was added carefully toTFA-(140 mL) and the solution warmed to 80° C. A solution of2,5-dinitrophenol (25 g, 0.192 mmol) in THF (60 mL) was added dropwiseto the reaction mixture and the reaction stirred for 3 hrs at 80° C. Thesolution was diluted with toluene and the TFA removed under reducedpressure. The solution was then poured into ice-water and extracted withethylacetate, washed successively with water, saturated aqueous NaHCO₃(to pH=6), water and brine, dried (MgSO₄), filtered and evaporated togive 17 g of crude 2,5-difluoro-4-hydroxybenzaldehyde use as this in thenext step.

To a solution of 2,5-difluoro-4-hydroxybenzaldehyde (37.5 g, 0.237 mmol)in dichloromethane (1.5 L) was added pyridinium tribromide (75.9 g,0.237 mmol). The reaction mixture was stirred at 400C for 7 hrs then atroom temperature overnight. The reaction was washed with water andbrine, dried over magnesium sulfate, filtered and evaporated to give48.4 g of crude 3-bromo-2,5-difluoro-4-hydroxybenzaldehyde use as thisin the next step.

To a solution of 3-bromo-2,5-difluoro-4-hydroxybenzaldehyde (48.4 g,0.193 mmol) in DMF (200 mL) was added potassium carbonate (40.0 g) anddimethylsulfate (27.4 mL). The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted wit ethylacetate andwashed successively with water and brine, dried over magnesium sulfate,filtered and evaporated. The residue was triturated with hexane toafford 26 g of 3-bromo-2,5-difluoro-4-methoxy benzaldehyde. The motherliquor was evaporated and chromatographed on silica gel (0-10% ethylacetate in hexane) to give 10.86 g of more product. (38% overall yieldfrom 2,5-dinitrophenol).

Example 145-[4-Ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 14”

Prepared in a similar manner to example 1 using4-ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.86% yield after crystallisation from dichloromethane and hexane. mp283-2850C. ¹H-NMR (300 MHz, DMSO-d-6): 1.08 (t, J=7.0 Hz, 3H), 1.09 (t,J=7.0 Hz, 3H), 1.25 (s, 3H), 1.28 (s, 3H), 2.06 (s, 3H), 2.45 (d, J=3.5Hz, 2H), 3.22 (m, 2H), 3.95 (m, 2H), 5.19 (t, J=5.9 Hz, 1H), 6.83 (d,J=8.8 Hz, 1H), 6.89 (s, 1H), 7.14 (d, J=2.3 Hz, 1H), 7.30 (s, 1H), 7.46(dd, J₁=8.8 Hz J₂=2.3 Hz, 1H), 7.69 (s, 1H).

a.4-ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.

The intermediate4-ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-benzaldehydewas prepared in a similar manner to example 7a using7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example2b) and 3-bromo-4-ethylamino benzaldehyde. 53% yield. ¹H NMR (300 MHz;CDCl₃): 1.21 (t, J=6.9 Hz, 3H), 1.31 (s, 3H), 1.35 (s, 3H), 2.08 (s,3H), 2.53 (s, 2H), 3.27 (m, 2H), 4.02 (q, J=7.5 Hz, 1H), 6.75 (d, J=8.7Hz, 1H), 6.83 (s, 1H), 7.21 (s, 1H), 7.52 (s, 1H), 7.81 (d, J=8.4 Hz,1H), 9.76 (s, 1H).

b. 3-bromo-4-ethylamino benzaldehyde.

To a solution of 4-diethylamino-benzaldehyde (10 g, 56.4 mmol) indichloromethane (300 mL) was added at room temperature pyridiumtribromide (54 g, 169.2 mmol). The reaction mixture was stirred at roomtemperature for 48 hrs, then it was washed successively with water andbrine, dried (MgSO₄), filtered and evaporated. The residue waschromatographed on silica gel (10% ethyl acetate in hexane) to give 10.3g of 3-bromo-4-ethylamino benzaldehyde (80%). ¹H NMR (300 MHz; CDCl₃):1.38 (t, J=6.9 Hz, 3H), 3.31 (m, 2H), 4.92 (br s, 1H), 6.67 (d, J=9 Hz,1H), 7.69 (dd, J₁=1.5 Hz, J₂=8.1 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 9.68(s, 1H).

Example 156-[2-Dimethylamino-5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione,which can be referred to as “Compound 15”

Prepared in a similar manner to example 1 using4-Dimethylamino-3-(1,4,7-trimethyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)-benzaldehyde(8%). mp 247-251° C. ¹H-NMR (300 MHz, DMSO-d-6): 2.15 (s, 3H), 2.58 (s,6H), 3.51 (s, 3H), 3.57 (s, 3H), 7.12 (d, J=8.8 Hz, 1H), 7.26 (s, 1H),7.28 (d, 1H, J=2.3 Hz), 7.36 (s, 1H), 7.50 (dd, J₁=2.3 Hz, J₂=8.8 Hz,1H), 7.72 (s, 1H), 12.4 (br s, 1H).

The intermediate4-Dimethylamino-3-(1,4,7-trimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)-benzaldehydewas prepared in a similar manner to example 3a using6-dimethylamino-3-formyl-1-phenyl boronic acid (example 3b) and6-bromo-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione (18%). ¹H NMR(300 MHz; CDCl₃): 2.12 (s, 3H), 2.69 (s, 6H), 3.65 (s, 6H), 7.1-7.6 (m,5H), 9.84 (s, 1H).

a. 6-bromo-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione.

To a solution of 1,4,6-trimethyl-1,4-dihydro-quinoxaline-2,3-dione (0.66g, 3.2 mmol) in acetic acid (40 mL) was added bromine (0.52 g, 3.2 mmol)and the solution stirred at 50° C. overnight. The reaction mixture wascooled to room temperature and poured into water. The solution wasneutralized with aqueous NaOH to Ph=7, extracted with dichloromethaneand washed with brine, dried (MgSO₄), filtered and evaporated to give0.9 g of 6-bromo-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione usedwithout further purification in the Suzuki coupling (step a). ¹H NMR(300 MHz; CDCl₃): 2.47 (s, 3H), 3.64 (s, 6H), 7.09 (s, 1H), 7.40 (s,1H).

b. 1,4,6-trimethyl-1,4-dihydro-quinoxaline-2,3-dione.

To a solution of 6-methyl-1,4-dihydro-quinoxaline-2,3-dione (5.3 g, 30mmol) in THF (150 mL) was added, at 0° C. under argon, sodium hydride(3.68 g, 80% in mineral oil, 120 mmol) followed by methyl iodide (7.5mL, 120 mmol). The solution was stirred at 0° C. for 3 hrs and at roomtemperature overnight. The reaction mixture was cooled to 0° C. andacidified with 1N HCl. The solution was extracted with dichloromethanewashed with brine, dried (MgSO₄), filtered and evaporated. The residuewas chromatographed on silica gel (10 to 25% acetonitrile indichloromethane) to give 1.1 g of1,4,6-trimethyl-1,4-dihydroquinoxaline-2,3-dione (18%). ¹H NMR (300 MHz;CDCl₃): 2.44 (s, 3H), 3.66 (s, 6H), 7.06-7.15 (m, 3H).

c. 6-methyl-1,4-dihydro-quinoxaline-2,3-dione.

3,4-Diaminotoluene (24.4 g, 0.2 mmol) was dissolved in 2N HCl (300 mL),oxalic acide dihydrate (27.7 g, 0.22 mmol) was added and the mixture washeated at reflux for 3.5 hrs. The reaction mixture was cooled to roomtemperature, filtered, washed with water, dried (MgSO₄), filtered andevaporated to give 34 g of 6-methyl-1,4-dihydro-quinoxaline-2,3-dione(96%). ¹H NMR (300 MHz; CDCl₃): 2.25 (s, 3H), 6.87-6.99 (m, 3H), 11.87(br s, 2H).

Example 165-[3-(1-Benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 16”

Prepared in a similar manner to example 1 using3-(1-Benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoromethoxy-benzaldehyde.72% yield. ¹H-NMR (300 MHz, DMSO-d-6): 1.37 (s, 6H), 2.03 (s, 3H), 4.89(s, 2H), 6.77 (s, 1H), 7.28 (m, 5H), 7.37 (s, 1H), 7.48 (d, J=2.0 Hz,1H), 7.61 (dd, J=1.6 Hz and 8.8 Hz, 1H), 7.74 (dd, J=2.3 Hz and 8.8 Hz,1H), 7.82 (s, 1H), 12.71 (br s, 1H).

a.3-(1-Benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoromethoxy-benzaldehyde.

The intermediate3-(1-Benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoromethoxy-benzaldehydewas prepared in a similar manner to example 1a using3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (Example 1b) andtrifluoro-methanesulfonic acid1-benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester. 27%yield. ¹H NMR (300 MHz; CDCl₃): 1.48 (s, 6H), 2.07 (s, 3H), 4.89 (s,2H), 6.50 (s, 1H), 1.74 (t, J=6.0 Hz, 2H), 2.01 (s, 3H), 2.69 (s, 6H),2.91 (dd, J=7.2 and 14.7 Hz, 1H), 7.13 (s, 1H), 7.27 (m, 5H), 7.47 (d,J=8.4 Hz, 1H), 7.71 (s, 1H), 7.93 (d, J=8.4 Hz, 1H)), 9.99 (s, 1H).

b. Trifluoro-methanesulfonic acid1-benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester.

To a solution of1-benzyl-6-hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (1.85 g, 6.60mmol) in anhydrous dichloromethane (30 mL) was added slowly, under argonat 0° C., pyridine (0.64 mL, 7.92 mmol) followed by triflic anhydride(1.33 mL, 7.92 mmol). The reaction was warmed up to room temperature andstirred overnight. The mixyure was washed successively with water, 1NHCl, water, saturated aqueous NaHCO₃, water and brine. The organicextract was dried over MgSO₄, filtered and evaporated to give 2.6 g oftrifluoro-methanesulfonic acid1-benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester (95%yield). ¹H NMR (300 MHz; CDCl₃): 1.42 (s, 6H), 2.31 (s, 3H), 4.87 (s,2H), 6.55 (s, 1H), 7.09 (s, 1H), 7.29 (m, 5H).

c. 1-benzyl-6-hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one.

To a solution of1-benzyl-6-methoxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (1.52 g, 5.15mmol) in anhydrous dichloromethane (50 mL) was added slowly, under argonat −78° C., BBr₃ (0.87 mL, 9.27 mmol). The reaction was warmed up to−20° C. and stirred overnight at room temperature. Water and the layerseparated. The aqueous layer was neutralized with NaHCO₃ and extractedwith dichloromethane. The organic combined extract was washed withaqueous NaHCO₃, water and brine, dried over MgSO₄, filtered andevaporated to give1-benzyl-6-hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (93% yield).¹H NMR (300 MHz; CDCl₃): 1.38 (s, 6H), 2.19 (s, 3H), 4.82 (s, 2H), 5.47(br s, 1H), 6.26 (s, 1H), 6.93 (s, 1H), 7.26 (m, 5H).

d. 1-benzyl-6-methoxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one.

To a solution ofN-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (4.35 g,11.56 mmol) in 1,4-dioxane (115 mL) was added sodium tert-butoxide (1.66g, 17.34 mmol). The mixture was degassed under argon for 30 minutes,then palladium (II) acetate (130 mg, 0.58 mmol) andtricyclohexylphosphine (162 mg, 0.58 mmol) were added and the mixturerefluxed overnight. A solution of saturated aqueous ammonium chloridewas added and the solution extracted with ethyl acetate. The organicextract was washed successively with water and brine, dried over MgSO₄,filtered and evaporated. The residue was chromatographed on silica gel(20% ethyl acetate in hexane) to give 1.94 g of1-benzyl-6-methoxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (57% yield).¹H NMR (300 MHz; CDCl₃): 1.40 (s, 6H), 2.16 (s, 3H), 3.67 (s, 3H), 4.90(s, 2H), 6.26 (s, 1H), 6.96 (s, 1H), 7.27 (m, 5H).

e. N-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide.

A mixture of powdered KOH (1.3 g, 23.13 mmol) in DMSO (25 mL) wasstirred at 0° C. for 5 minutes.N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (3.30 g, 11.56 mmol)was added cautiously followed immediately by the addition ofbenzylbromide (2.75 mL, 23.13 mmol) and the reaction stirred at roomtemperature for 48 hrs. Water was added and the mixture extracted withethyl acetate. The organic extract was washed successively with waterand brine, dried over MgSO₄, filtered and evaporated. The residue waschromatographed on silica gel (20% ethyl acetate in hexane) to give 4.3g of N-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99%yield). ¹H NMR (300 MHz; CDCl₃): 1.02 (d, J=6.6 Hz, 3H), 1.15 (d, J=6.6Hz, 3H), 2.16 (s, 3H), 2.29 (m, 1H), 3.43 (s, 3H), 3.85 (d, J=14.1 Hz,1H), 5.75 (d, J=14.1 Hz, 1H), 6.02 (s, 1H), 7.18-7.27 (m, 5H), 7.38 (s,1H).

f. N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide.

To a biphasic mixture of 2-bromo-5-methoxy-4-methyl-aniline (5.6 g,25.96 mmol), 10% KOH (27 mL) and dichloromethane (30 mL), was addeddropwise isobutyryl chloride (3 mL, 28.55 mmol) in dichloromethane (10mL). The reaction mixture was stirred at room temperature for 48 hrs.The layers were separated. The aqueous layer was further extracted withdichloromethane and the combined organics washed successively with waterand brine, dried over MgSO₄, filtered and evaporated to give 7.38 g ofN-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99% yield). ¹H NMR(300 MHz; CDCl₃): 1.29 (d, J=6.9 Hz, 6H), 2.14 (s, 3H), 2.59 (m, 1H),3.84 (s, 3H), 7.24 (s, 1H), 7.66 (br s, 1H), 8.07 (s, 1H).

g. 2-bromo-5-methoxy-4-methyl-aniline.

To a solution of 3-methoxy-4-methyl-aniline (8.19 g, 59.71 mmol) indichloromethane (200 mL), was added tetrabutylammonium tribromide (28.79g, 59.71 mmol) and the reaction mixture was stirred at room temperaturefor 2.5 hrs. Aqueous NaHCO₃ was added and the layers separated. Theaqueous layer was further extracted with dichloromethane and thecombined organics washed successively with water and brine, dried overMgSO₄, filtered and evaporated. The residue was chromatographed onsilica gel (20% ethyl acetate in hexane) to give 11.05 g of2-bromo-5-methoxy-4-methyl-aniline (85% yield). ¹H NMR (300 MHz; CDCl₃):2.09 (s, 3H), 3.75 (s, 3H), 3.95 (br s, 1H), 6.27 (s, 1H), 7.13 (s, 1H).

h. 3-methoxy-4-methyl-aniline.

To a solution of 2-methyl-5-nitroanisole (11.56 g, 69.2 mmol) in amixture of ethyl acetate (200 mL) and ethanol (70 mL) was addedportionwise tin (II) chloride dihydrate (109 g, 0.483 mol) and themixture was stirred at room temperature overnight. The reaction mixturewas basified with aq. K₂CO₃ and filtered over celite. The layers wereseparated.

The aqueous layer was further extracted with ethyl acetate and thecombined organics washed successively with water and brine, dried overMgSO₄, filtered and evaporated to give 8.02 g of3-methoxy-4-methyl-aniline (86% yield). ¹H NMR (300 MHz; CDCl₃): 2.09(s, 3H), 3.76(s, 3H), 4.01 (br s, 1H), 6.20 (m, 2H), 6.90 (d, J=8.4 Hz,1H).

Example 175-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-5-fluoro-4-methoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 17”

Prepared in a similar manner to example 1 using3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-5-fluoro-4-methoxy-benzaldehyde.36% yield, mp 260-262° C. ¹H-NMR (300 MHz, DMSO-d-6): 1.08 (t, J=6.7 Hz,3H), 1.25 (s, 6H), 2.09 (s, 3H), 2.46 (s, 2H), 3.83 (s, 3H), 3.96 (q,J=6.7 Hz, 2H), 6.98 (s, 1H), 7.25 (br s, 1H), 7.28 (s, 1H), 7.56 (dd,J₁=12.6 Hz, J₂=2.0 Hz, 1H), 7.80 (s, 1H), 12.67 (br s, 1H).

The intermediate3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-5-fluoro-4-methoxy-benzaldehydewas prepared in a similar manner to example 7a using7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example2b) and 3-bromo-5-fluoro-4-methoxy-benzaldehyde. 12% yield. ¹H-NMR (300MHz, CDCl₃): 1.23 (t, J=7.0 Hz, 3H), 1.33 (s, 6H), 2.13 (s, 3H), 2.53(s, 2H), 3.91 (s, 3H), 4.01 (q, J=7.0 Hz, 2H), 6.83 (s, 1H), 7.19 (s,1H), 7.50 (d, J=1.8 Hz, 1H), 7.66 (dd, J₁=11.7 Hz, J₂=2.1 Hz, 1H), 9.91(s, 1H).

The intermediate 3-bromo-5-fluoro-4-methoxy-benzaldehyde was prepared ina similar manner to example 5d using 3-fluoro-4-methoxy-benzaldehyde. Itwas used without purification in the next step. ¹H-NMR (300 MHz, CDCl₃):4.11 (s, 3H), 7.60 (d, J=11.1 Hz, 1H), 7.87 (s, 1H), 9.87 (s, 1H).

Example 185-(1′-Ethyl-4′,4′,6′-trimethyl-2′-oxo-1′,2′,3′,4′-tetrahydro-[4,7′]biquinolinyl-2-ylmethylene)-thiazolidine-2,4which can be referred to as “Compound 18”

Prepared in a similar manner to example I using1′-Ethyl-4′,4′,6′-trimethyl-2′-oxo-1′,2′,3′,4′-tetrahydro-[4,7′]biquinolinyl-2-carbaldehyde.mp 299-301° C. ¹H-NMR (300 MHz, DMSO-d-6): 1.05 (t, J=7.2 Hz, 3H); 1.28(s, 3H); 1.33 (s, 3H); 1.97 (s, 3H); 3.94 (q, J=6.0 Hz, 2H); 7.06 (s,1H); 7.40 (s, 1H); 7.49 (d, J=8.4 Hz, 1H); 7.64 (t, J=7.2 Hz, 1H); 7.86(t, J=7.5 Hz, 1H); 7.90 (s, 1H); 8.01 (s, 1H); 8.22 (d, J=8.1, 1H);12.54 (br s, 1H).

a.1′-Ethyl-4′,4′,6′-trimethyl-2′-oxo-1′,2′,3′,4′-tetrahydro-[4,7′]biquinolinyl-2-carbaldehyde.

A mixture of1-Ethyl-4,4,′-trimethyl-2-oxo-1,2,3,′-tetrahydro-quinoline-7-boronicacid (0.25 g, 0.96 mmol),4-trifluoromethanesulfonyloxy-quinoline-2-carbaldehyde (example 18 d)(0.17 g, 0.80 mmol) and potassium carbonate (0.21 g, 1.6 mmol) intoluene (5 mL), ethanol (1 mL) and water (0.75 mL) was degassed withargon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (20 mg,0.016 mmol) was added and the mixture heated at reflux under argon for20 hrs. The solution was cooled to room temperature, diluted with ethylacetate and washed successively with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated. The residue waspurified on silica gel (0%-20% ethyl acetate in hexane) to give 0.18 gof1′-Ethyl-4′,4′,6′-trimethyl-2′-oxo-1′,2′,3′,4′-tetrahydro-[4,7′]biquinolinyl-2-carbaldehyde(52%). ¹H NMR (300 MHz; CDCl₃): 1.20 (t, J=7.2 Hz, 3H), 1.35 (s, 3H),1.39 (s, 3H), 1.99 (s, 3H), 2.56 (s, 2H), 4.00 (br d, 2H), 6.86 (s, 1H),7.26 (d, J=2.7 Hz, 1H), 7.62 (d, J=3.6 Hz, 1H), 7.83 (m, J=1H), 7.92 (s,1H), 8.33 (d, J=8.4 Hz, 1H), 10.29 (s, 1H).

b. 1-Ethyl-4,4,′-trimethyl-2-oxo-1,2,3,′-tetrahydro-quinoline-7-boronicacid.

To a solution of1-Ethyl-4,4,6-trimethyl-7-(4,45,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one(13.8 g, 40.20 mmol) in dichloromethane (150 mL), was added dropwiseunder argon at −78° C. boron tribromide (19 mL, 201 mmol) and thesolution slowly warmed up to room temperature and left overnight at roomtemperature. The solution was poored on ice-water slowly and extractedwith ethylacetate, washed successively with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated. The residue wasrecrystalised from ethylacetate and hexane to give1-ethyl-4,4,′-trimethyl-2-oxo-1,2,3,′-tetrahydro-quinoline-7-boronicacid (9 g, 86% yield). ¹H NMR (300 MHz; CDCl₃): 1.06 (t, J=7.5 Hz, 3H),1.12 (s, 6H), 2.30 (s, 3H), 3.84 (br d, 2H), 7.05 (s, 1H), 7.11 (s, 1H).

c.1-Ethyl-4,4,6-trimethyl-7-(4,45,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one.

To a solution of7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example2b) (6.5 g, 91.95 mmol) in dioxane (65 mL), were added dropwise underargon triethylamine (12.3 mL, 87.78 mmol), palladium(II)acetate (0,246g, 1.098 mmol), 2-(dicyclohexylphosphino)biphenyl (1.54 g, 4.39 mmol)and pinacolborane (9,6 mL, 65.85 mmol). The reaction mixture was heatedat 85° C. for 3 hours then cooled to room temperature. Water (7 mL) wasadded slowly to the mixture followed by a saturated aqueous solution ofammonium chloride (100 mL). The mixture was extrated with ethylacetateand washed successively with water and brine, dried over anhydrousmagnesium sulfate, filtered and evaporated. The crude was purified onsilica gel (0-20% ethylacetate in hexane) to give1-Ethyl-4,4,6-trimethyl-7-(4,45,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one(5.1 g, 67% yield). ¹H NMR (300 MHz; CDCl₃): 1.24 (m, 9H), 1.31 (s,12H), 2.45 (s, 2H), 2.51 (s, 3H), 4.09 (m, 2H), 7.09 (s, 1H), 7.42 (s,1H).

d. 4-trifluoromethanesulfonyloxy-quinoline-2-carbaldehyde.

To a solution of 4-trifluoromethanesulfonyloxy-quinoline-2-carboxylicacid ethyl ester (4.5 g, 12.88 g) in toluene (80 mL) was added slowlyunder argon at −78° C. diisobuthylaluminum hydride (1.5M in toluene,12.88 mL, 19.33 mmol). The reaction mixture was stirred at −78° C. for 1hour. Methanol (13 mL) was added slowly followed by water (26 mL). Thereaction mixture was slowly warmed up to room temperature extracted withethylacetate and washed with brine, dried over magnesium sulfate,filtered and evaporated. The residue was purified on silica gel (5-10%ethylacetate in hexane) to give 2.9 g of4-trifluoromethanesulfonyloxy-quinoline-2-carbaldehyde (74%). ¹H NMR(300 MHz; DMSO-d₆): 8-8.2 (m, 4H), 8.43 (m, 1H), 10.05 (s, 1H).

e. 4-trifluoromethanesulfonyl-quinoline-2-carboxylic acid ethyl ester.

To a solution of 4-hydroxy-quinoline-2-carboxylic acid ethyl ester (3.7g, 17.03 g) in dichloromethane (100 mL) was added slowly under argonpyridine (1.65 mL, 20.44 mmol). The reaction mixture was cooled to 0° C.then trific anhydride (3.44 mL, 20.44 mmol) was added dropwise. Thereaction mixture was slowly warmed up to room temperature and stirred atroom temperature overnight. The solution was successively washed withwater, 1N HCl, water, sat. NaHCO₃, water and brine, dried over magnesiumsulfate, filtered and evaporated. The residue was purified on silica gel(5-15% ethylacetate in hexane) to give 4.5 g of4-trifluoromethanesulfonyl-quinoline-2-carboxylic acid erthyl ester(76%).

Example 195-[2,5-Difluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dionewhich can be referred to as “Compound 19”

Prepared in a similar manner to example 1 using2,5-Difluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.mp 165-167° C. ¹H-NMR (300 MHz, DMSO-d-6): δ 1.27 (s, 6H); 2.06 (s, 3H);2.49 (s, 2H); 3.24 (s, 3H); 3.81(d, J=1.8 Hz, 3H); 6.98 (s, 1H); 7.31(s, 1H); 7.46 (dd, J₁=7.2 Hz, J₂=12.3 Hz, 1H); 7.70(s, 1H); 12.77 (s,1H).

a.2,5-Difluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-benzaldehyde.

A mixture of1,4,4,6-tetramethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinoline-2-one(0.36 g, 1.1 mmol), 3-bromo-2,5-difluoro-4-methoxybenzaldehyde (example13 a) (0.25 g, 0.1 mmol) and potassium carbonate (0.275 g, 1.99 mmol) intoluene (5 mL), ethanol (1 mL) and water (0.75 mL) was degassed withargon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (58 mg,0.05 mmol) was added and the mixture heated at reflux under argon for 20hrs. The solution was cooled to room temperature, diluted with ethylacetate and washed successively with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated. The residue waspurified on silica gel (0%-20% ethyl acetate in hexane) to give 97 mg of2,5-Difluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.

b.1,4,4,6-tetramethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinoline-2-one.

To a solution of7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (example 1d)(1 g, 3.54 mmol) in dioxane (10 mL), were added dropwise under argontriethylamine (1.98 mL, 14.175 mmol), palladium(II)acetate (39.8 mg,1.772 mmol), 2-(dicyclohexylphosphino)biphenyl (248 mg, 0.709 mmol) andpinacolborane (1.54 mL, 10.632 mmol). The reaction mixture was heated at85° C. for 1.5 hours then cooled to room temperature. Water (1 mL) wasadded slowly to the mixture followed by a saturated aqueous solution ofammonium chloride. The mixture was extrated with ethylacetate and washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The crude was purified on silica gel(25% ethylacetate in hexane) to give1,4,4,6-tetramethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinoline-2-one(0.91 g, 78% yield).

Example 205-[4-Trifluoromethoxy-3-(4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 20”

Prepared in a similar manner to example 1 using4-Trifluoromethoxy-3-(4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.76% yield. mp 306-308° C. ¹H-NMR (300 MHz, DMSO-d-6): ¹H NMR (300 MHz:DMSO): 1.26 (s, 3H); 1.29 (s, 3H); 2.04 (s, 3H); 2.38 (m, 2H); 6.69 (s,1H); 7.26 (s, 1H); 7.58 (d, J=1.8 Hz, 1H); 7.64 (dd, J₁=1.2 Hz, J₂=8.7Hz, 1H); 7.74 (dd, J₁=2.4 Hz, J₂=8.7 Hz., 1H); 7.86 (s, 1H); 10.16 (s,1H); 12.71 (br. s, 1H)

The intermediate4-Trifluoromethoxy-3-(4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-benzaldehydewas prepared in a similar manner to example 1a using7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (Example 1e) and3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (example 1b).

Example 215-[3-(1-Ethyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 21”

Prepared in a similar manner to example 1 using3-(1-Ethyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoromethoxy-benzaldehyde.51% yield. ¹H-NMR (300 MHz, DMSO-d-6): 1.1 (t, J=7.03 Hz, 3H), 1.30 (s,6H), 2.07 (s, 3H), 3.70 (q, J=7.33 Hz, 2H), 6.91 (s, 1H), 7.34 (s, 1H),7.65-7.68 (m, 2H), 7.75 (dd, J₁=2.35, J₂=8.79 Hz, 1H), 7.88 (s, 1H),12.7 (bs, 1H).

a.3-(1-Ethyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoromethoxy-benzaldehyde.

To a solution of4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzaldehyde(210 mg, 0.58 mmol) in DMSO (5 mL) was added KOH (powder, 65 mg, 1.16mmol) and iodoethane (180 mg, 1.16 mmol) under argon. The mixture wasstirred at room temperature for about 2 hours. 5 mL of water was added,the product was extracted with EtOAc, washed with brine, dried overMgSO₄, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane:EtOAc/4:1). 120mg of pale colorles solid was obtained (yield: 53%). ¹H NMR (300 MHz,CDCl₃, ppm): δ: 1.24 (t, J=7.03 Hz, 3H), 2.10 (s, 3H), 3.74 (m, 2H),6.65 (s, 1H), 7.12 (s, 1H), 7.53 (dd, J₁=1.76 Hz, J₂=8.50 Hz, 1H), 7.85(d, J=2.34 Hz, 1H), 7.96 (dd, J₁=2.34 Hz, J₂=8.50 Hz, 1H), 10.05 (s,1H).

b.-Trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzaldehyde

A mixture of trifluoro-methanesulfonic acid3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester (243 mg, 0.75mmol), 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (Example 1b)(194 mg, 0.83 mmol) in toluene (10 mL), EtOH (1.5 mL) and water (1 mL)was deassed with argon for 20 minutes.Tetrakis(triphenylphosphine)palladium(0) (398 mg, 0.34 mmol), sodiumcarbonate (159 mg, 1.50 mmol) and lithium chloride (98 mg, 2.25 mmol)were added and the reaction mixture was heated to reflux under argon for22 hours. The reaction was cooled to room temperature, diluted withethylacetate and washed successively with water and brine, dried overMgSO₄, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane:EtOAc/3:1) togive 166 mg of4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzaldehyde(61%). ¹H NMR (300 MHz, CDCl₃, ppm): δ: 1.44 (s, 6H), 2.09 (s, 3H), 6.72(s, 1H), 7.10 (s, 1H), 7.50-7.53 (m, 1H), 7.82 (d, J=2.34 Hz, 1H),7.94-7.97 (m, 2H), 10.03 (s, 1H).

c. Trifluoro-methanesulfonic acid3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester

To a solution of 6-Hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (640mg, 3.17 mmol) in dichloromethane (15 mL) was added at 0° C.triethylamine (642 mg, 884 uL, 6.34 mmol) followed by slow addition oftrifluomethanesulfonic anhydride (984 mg, 586 uL, 3.49 mmol). Themixture was slowy warmed to room temperature and stirred at roomtemperature overnight. The solution was washed with water and brine,dried over MgSO₄, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel(hexane:EtOAc/2:1) to give 750 mg of trifluoromethanesulfonic acid3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester (73%). ¹H NMR (300MHz, CDCl₃, ppm): δ: 1.40 (s, 6H), 2.35 (s, 3H), 6.82 (s, 1H), 7.09 (s,1H), 8.10 (bs, 1H).

d. 6-Hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one

6-Methoxy-1-(4-methoxy-benzyl-3,3,5-trimethyl-1,3-dihydro-indol-2-one(640 mg, 1.97 mmol) was mixed with acetic acid (0.7 mL) and 48%hydrobromic acid (7 mL) and heated to reflux 12 hours. The solution wascooled to 0° C. and aqueous Na₂CO₃ was added to adjust to pH=7 thenextracted with EtOAc, washed with brine, dried over MgSO₄, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane:EtOAc/4:1 to 1:1) to give 280 mg of6-Hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (74%). ¹H NMR (300MHz, DMSO-d₆, ppm): δ: 1.15 (s, 6H), 2.026.34 (s, 1H), 6.89 (s, 1H),9.21 (s, 1H), 10.01(s, 1H).

e. 6-Methoxy-1-(4-methoxy-benzyl-3,3,5-trimethyl-1,3-dihydro-indol-2-one

To a solution ofN-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isobutyramide(8.72 g, 21.4 mmol) in dry 1,4-dioxane (80 mL) was added sodiumtert-butoxide (3.09 g, 32.1 mmol). Argon was bubbled through for about15 minutes before adding palladium(II) acetate (241 mg, 1.07 mmol) andtricyclohexylphosphine (300 mg, 1.07 mmol). The mixture was heated toreflux for 16 hours. The mixture was cooled to room temperature, dilutedwith water and extracted with EtOAc, washed with brine, dried overMgSO₄, filtered and evaporated. The residue was purified by columnchromatography on silica gel (hexane:EtOAc/5:1 to 3:1) to give 5.4 g of6-Methoxy-1-(4-methoxy-benzyl-3,3,5-trimethyl-1,3-dihydro-indol-2-one(77%). ¹H NMR (300 MHz, CDCl₃, ppm): δ: 1.38 (s, 6H), 2.16(s, 3H),3.71(s, 3H), 3.77 (s, 3H), 4.84 (s, 2H), 6.28 (s, 1H), 6.82-6.85(m, 2H),6.95(s, 1H), 7.19-7.22 (m, 2H).

f.N-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isobutyramide

To a solution of N-(2-bromo-5-methoxy-4-methyl-phenyl)isobutyramide(6.83 g) in DMSO (40 mL) was added powder KOH (2.68 g, 47.7 mmol) and4-methoxybenzyl chloride (7.5 g, 47.7 mmol) under argon. The mixture wasstirred at room temperature for 17 hours. Water (30 mL) was added andthe mixture extracted with EtOAc, washed with brine, dried over MgSO₄,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel (hexane:EtOAc/10:1 to 3:1) togive 8.72 g ofN-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isobutyramide(90%). ¹H NMR (300 MHz, CDCl₃, ppm): δ: 1.00 (d, J=7.03 Hz, 3H), 1.13(d, J=6.45 Hz, 3H), 2.17 (s, 3H), 2.28 (m, 1H), 3.48 (s, 3H), 3.78(s,3H), 3.84 (d, J=14.07 Hz, I H), 5.62 (d, J=14.07 Hz, 1H), 6.06 (s, 1H),6.78-6.81 (m, 2H), 7.10-7.13 (m, 2H), 7.38 (s, 1H).

g. N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide

To a solution of N-(3-methoxy-4-methyl-phenyl)-isobutyramide (5.0 g,24.1 mmol) in dichloromethane (200 mL) was added tetrabutylammoniumtribromide (12.2 g, 25.3 mmol) at 0° C. The mixture was then stirred atroom temperature for 20 hours. The solution was washed with water,brine, aqueous sodium bicarbonate solution, brine, dried over MgSO₄,filtered and evaporated under reduced pressure to give 6.83 g ofN-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99%). ¹H NMR (300MHz, CDCl₃, ppm): δ: 1.29 (d, J=7.03 Hz, 6H), 2.15 (s, 3H), 2.59 (m,1H), 3.84 (s, 1H), 7.24 (s, 1H), 7.65 (bs, 1H), 8.08 (s, 1H).

h. N-(3-methoxy-4-methyl-phenyl)-isobutyramide

N-(3-hydroxy-4-methyl-phenyl)-isobutyramide (6.48 g, 33.5 mmol) wasdissolved in 40 mL of acetone, potassium carbonate (13.9 g, 100.5 mmol)was added followed by methyl iodide (14.3 g, 100.5 mmol). The mixturewas stirred at room temperature for about 3 days. The solution wasfiltered and evaporated under reduced pressure to give 6.6 g ofN-(3-methoxy-4-methyl-phenyl)-isobutyramide (95%). ¹H NMR (300 MHz,CDCl₃, ppm): δ: 1.26 (d, J=7.03 Hz, 6H), 2.17 (s, 3H), 2.49 (m, 1H),3.83 (s, 3H), 6.71 (dd, J=2.05 Hz, 8.21 Hz, 1H), 7.02 (d, J=7.91 Hz,1H), 7.11 (bs, 1H), 7.47 (d, J=1.76 Hz, 1H).

i. N-(3-hydroxy-4-methyl-phenyl)-isobutyramide

To a mixture of 5-amino-2-methylphenol (30 g, 244 mmol), 10% NaOH (210mL) and dichloromethane (120 mL) was added at 0° C. slowly isobuyrylchloride (25.5 mL, 244 mmol) in dichloromethane (50 mL). The mixture wasstirred at room temperature overnight. The aqueous layer was separatedand extracted with EtOAc, washed with brine, dried over MgSO₄, filteredand evaporated under reduced pressure to give 37.2 g ofN-(3-hydroxy-4-methyl-phenyl)-isobutyramide (78%). ¹H NMR (300 MHz,CDCl₃ ppm): δ: 1.21(d, J=7.03 Hz, 6H), 2.17(s, 3H), 2.53 (m, 1H), 2.58(s, 3H), 6.81(dd, J=2.05 Hz, 7.91 Hz, 1H), 6.97 (d, J=7.91 Hz, 1H), 7.38(d, J=2.05 Hz, 1H), 8.14 (bs, 1H), 8.58 (s, 1H).

Example 225-[4-Trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 22”

Prepared in a similar manner to example 1 using4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzaldehyde(example 21b; 58% yield. ¹H-NMR (300 MHz, DMSO-d-6): 1.29 (s, 6H), 2.03(s, 3H), 6.64 (s, 1H), 7.28 (s, 1H), 7.61-7.66 (m, 2H), 7.74 (dd,J=2.34, 8.79 Hz, 1H), 7.86(s, 1H), 10.33 (s, 1H), 12.71 (bs, 1H).

Example 235-[4-Trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-6-yl)-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 23”

Prepared in a similar manner to example 1 using4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-6-yl)-benzaldehyde.58% yield. ¹H-NMR (300 MHz, DMSO-d₆, ppm): 0.82 (t, J=7.33 Hz, 3H), 1.31(s, 6H), 1.58 (m, 2H), 2.06 (s, 3H), 3.62 (t, J=7.62 Hz, 2H), 6.91 (s,1H), 7.34 (s, 1H), 7.65 (d, J=2.35 Hz, 1H), 7.6 (m, 1H), 7.75 (dd,J=2.34, 8.79 Hz, 1H), 7.87 (s, 1H), 12.7 (bs, 1H).

The intermediate4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-6-yl)-benzaldehydewas prepared in a similar manner to example 21a using4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzaldehyde(example 21b) and propyl iodide. ¹H NMR (300 MHz, CDCl₃, ppm): δ:0.93(t, J=7.3 Hz, 3H), 1.45(s, 6H), 1.70(m, 2H), 2.10(s, 3H), 3.66 (m,2H), 6.63 (s, 1H), 7.11 (s, 1H), 7.52-7.55 (m, 1H), 7.85 (m, 1H), 7.98(m, 1H), 10.05 (s, 1H).

Example 245-[3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,which can be referred to as “Compound 24”

The synthesis and utility of Compound 24 was disclosed in U.S. Pat. No.6,515,003, issued Feb. 4, 2003, which is incorporated herein in itsentirety by this reference.

Example 255-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,TRIS salt, which can be referred to as “Compound 25”

Compound 2 (14.85 g, 29.37 mmol) was dissolved in dry THF (100 mL) and asolution of tris(hydroxymethyl)aminomethane (“Tris,” 3.56 g, 29.37 mmol)in dry methanol (20 mL0 was added dropwise at room temperature. Thereaction mixture was stirred 48 hrs at room temperature, filtered andevaporated. The residue was redissolved in ethanol, evaporated and driedunder high vacuum to afford 16.6 g of:5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione.TRIS. ¹H-NMR (300 MHz, DMSO-d-6): 1.06 (t, J=7.2 Hz, 3H); 1.26 (s, 6H),2.08 (s, 3H), 2.46 (s, 2H), 3.47 (s, 6H), 3.96 (br d, 2H), 5.16 (s, 3H),6.97 (s, 1H), 7.30 (s, 1H), 7.36(s, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.55(dd, J=1.5 Hz and 8.4 Hz, 1H), 7.68 (dd, J=2.1 Hz and 8.7 Hz, 1H).

Example 26 Differentiation of 3T3-L1 Pre-Adipocytes in an In VitroAssay. (See Results in FIG. 1)

The following protocol was used to determine adipocyte differentiationactivity of the compounds of the invention:

Mouse pre-adipocyte 3T3-L1 cells obtained from ATCC (American TissueCulture Collection, Md.) were initially grown in DME Dulbecco's modifiedEagle's medium containing 4500 mg/L glucose; 4 mM L-glutamine; 10 U/mlPen-G; 10 mcg/ml Streptomycin and 10% Bovine Calf Serum (CS) at 37° C.and 10% CO₂. Cells were plated in 96 well plates at a density ofapproximately 3,000 cells/well and grown to confluence (when cells use100% of the available space on the well) in the same medium.Differentiation experiments were conducted two days after confluence ina differentiation medium (DM) consisting of DME Dulbecco's modifiedEagle's medium containing 4500 mg/L glucose; 4 mM L-glutamine; 10 U/mlPen-G; 10 mcg/ml Streptomycin and 10% Fetal Calf Serum (FCS) and 1 μg/mLof insulin. Cells were then treated with the test compound at aconcentration of 10⁻¹⁰ to 10⁻⁶M, or with a control forfully-differentiated adipocytes, such as Dexamethasone/Insulin (2.5 μM;10 μg/ml, respectively). Differentiation medium containing thecompounds, with no further addition of insulin, was replaced every 2-3days for a total of 7 days. Compound 24 was used as a standard fordifferention activity, and its ability to differentiate 3T3-L1 cells at0.1 μM was taken as reference for 100% differentiation. Upon terminationof the experiments the treated cells were washed once with PBS(Phosphate Buffer Saline, Irvine Scientific, Irvine, Calif.) and lysedin situ with 50 μL 10% Hecameg (Detergent, Calbiochem, San Diego). Thecellular lysates were analyzed for their lipid content using theTriglyceride-GPO Trinder reagent from Sigma.

As shown in FIG. 1, many of compounds of the invention inducedifferenciation of 3T3-L1 cells.

Example 27 Oral Administration of Selected Compounds in the Treatment ofType 2 Diabetes in KKA^(y) Mice (FIG. 2 a-e)

The procedure for this in-vivo assay for anti-diabetes activity wasdescribed in detail by Iwatsuka, et al. (1970 General Survey of DiabeticFeatures of Yellow KK Mice. Endocrinol. Japon. 17: 23-35, incorporatedherein in its entirety by reference).

Experimental Procedures: Six to eight week-old male KKA^(y) mice(obtained from Jackson Labs of Bar Harbord, Me.) were housed in a fixed12-12-hr artificial light-dark cycle, and maintained on a standardrodent diet provided ad libitum. Animals were allowed two days toacclimate in this experimental environment prior to the initiation ofthe study.

Prior to initiation of treatment with the compounds of the invention,the animals were bled from the tail vein (100-200 μL of whole blood) andserum levels of glucose and triglycerides were measured in duplicate(Trinder kits; Sigma, St. Louis, Mo.). Based on these initial measures,animals were sorted into groups with approximately the same averageserum glucose levels. Once sorted, the animals were housed one per cageand provided rodent diet ad libitum. Unless otherwise indicated,compounds were suspended in sesame oil, and administered by oral gavageonce daily to animals in a volume of 3 ml/kg/dose.

Treatment Group A (n=5/group): (See Results in FIG. 2 a)

-   -   1) KKA^(y) vehicle control (sesame oil)    -   2) Compound 1 (3 mg/kg)    -   3) Compound 1 (10 mg/kg)    -   4) Compound 2 (3 mg/kg)    -   5) Compound 2 (10 mg/kg)

Treatment Group B (n=6/group): (See Results in FIG. 2 b)

-   -   1) KKA^(y) vehicle control (sesame oil)    -   2) Compound 11 (15 mg/kg)

Treatment Group C (n=6/group): (See Results in FIG. 2 c)

-   -   1) KKA^(y) vehicle control (sesame oil)    -   2) Compound 13 (15 mg/kg)

Treatment Group D (n=6/group): (See Results in FIG. 2 d)

-   -   1) KKA^(y) vehicle control (CMC)    -   2) Compound 25 (3 mg/kg, CMC)        Compound 25 was suspended in a solution of carboxymethyl        cellulose (CMC; 1% carboxy methyl cellulose in H₂O, with 10%        polyethelene glycol 400), and administered to animals in a        volume of 5 ml/kg/dose.

Treatment Group E (n=5/group): (See Results in FIG. 2 e)

-   -   1) KKA^(y) vehicle control (10% HPPCD)    -   2) Compound 25 (1 mg/kg)    -   3) Compound 25 (3 mg/kg)    -   4) Compound 25 (10 mg/kg)        Compound 25 was dissolved in a 10% hydroxy propyl beta        cyclodextrin solution, and administered to animals in a volume        of 10 ml/kg/dose.

To monitor the effect of the tested compounds, animals were bled at theend of the dark cycle on days 7, 14, and/or 21 of the treatment period.Serum glucose, triglyceride and/or cholesterol levels were measured induplicate. The blood is kept at room temperature to allow coagulation,after which the serum is separated and assayed for glucose, triglycerideand/or cholesterol levels. As shown in FIGS. 2 a-2 d all of thecompounds tested reduced serum glucose and triglyceride levels, somewith doses as low as 3 mg/kg when administered once a day. Also, asshown in FIG. 2 e compound 25 causes an unexpectedly strong andsimultaneous reduction in serum glucose, triglyceride and totalcholesterol levels of type 2 diabetic KKAy mice following 4 weeks oftreatment.

Example 28 Oral Administration of Selected Compounds in the Treatment ofType 2 Diabetes in db/db Mutant Mice (See Results in FIG. 3)

Experimental Procedure: Seven week-old female db/db mutant mice(C57BL/KsJ-db+/+m; Jackson Labs, Bar Harbour, Me.) were housed in afixed 12-12-hr artificial light-dark cycle, and maintained on a standardhigh fat diet (containing at least 11% crude fat) provided ad libitum(Teklad S-2335). Animals were allowed two days to acclimate in thisexperimental environment prior to the initiation of the study. Prior toinitiation of treatment, the animals were bled from the tail vein(100-200 μL of whole blood) and serum levels of glucose andtriglycerides were measured in duplicate (Trinder kits; Sigma, St.Louis, Mo.). Based on these initial measures, animals were sorted intotreatment groups with approximately the same average serum glucoselevels. Once sorted, the animals were housed five per cage and providedhigh fat rodent diet ad libitum.

Treatment groups (n=5/group):

-   -   1) db/db control (CMC)    -   2) Compound 25 (0.1 mg/kg, in CMC)    -   3) Compound 25 (0.3 mg/kg, in CMC)    -   4) Compound 25 (1 mg/kg, in CMC)

Compound 25 was suspended in a solution of carboxymethyl cellulose (CMC;1% carboxy methyl cellulose in H₂O, with 10% polyethelene glycol 400),and administered to animals in a volume of 5 ml/kg/dose. The drug isadministered by oral gavage once daily at the beginning of theartificial light cycle.

To monitor the effect of the tested compounds, animals were bledfollowing a three-hour fast at the end of the dark cycle on days 0, 7,14 of the treatment period. Fasting serum glucose and triglyceridelevels were measured in duplicate. The blood is kept at room temperatureto allow coagulation, after which the serum is separated and assayed forglucose and triglyceride levels. As shown in FIG. 3, compound 25ameliorate the symptoms of diabetes in with doses as low as, 0.3 mg/kgwhen administered once daily. Both serum glucose and triglyceride werereduced compared to control animals, which showed the typicalhyperglycemia and hypertriglyceridemia associated with type 2 diabetes.

Example 29 Cholesterol Efflux Assay from Macrophage Foam Cells asInduced by Compound 2. (See Results in FIG. 4)

Cholesterol efflux from macrophage foam cells was assayed as describedby Sparrow. et al, J. Biol. Chem., 2002, 277, 10021-10027, which isencorporated herein in its entirety by this reference. THP-1 cellsobtained from ATCC (Manassas, VI), were cultured in RPMI medium (Sigma,St-Louis, Mo.), containing 10% fetal calf serum (Sigma, St-Louis, Mo.),0.05 μM 2-mercaptoethanol, 1 mM sodium pyruvate, 2 mM L-glutamine, 100units/ml penicillin, 0.1 μg/ml streptomycin and 0.25 μg/ml amphotericinB obtained from Sigma (St-Louis, Mo.). The THP-1 cells weredifferentiated into macrophages in 24 well tissue culture dishes at adensity of 0.5 million cells/well by incubation in the same medium plus100 nM tetradecanoyl phorbol acetate (Sigma, St-Louis, Mo.), for 3 days.

After differentiation into macrophages, the cells were tested forcholesterol efflux as induced by compound 2 of the invention. Cells werelabeled by incubation for 24 hr in fresh growth medium containing[3H]-cholesterol (10 μCi/ml) (PerkinElmer, Boston, Mass.), and 50 μg/mlacetylated-LDL (Frederick, Md.) and 1% Fetal bovine serum (Sigma,St-Louis, Mo.). Following labeling with [3H]-cholesterol, cells werewashed, and incubated for an additional 24 hr in serum-free mediacontaining 1 mg/ml bovine serum albumin (Sigma, St-Louis, Mo.), to allowfor equilibration of [3H]-cholesterol with intracellular cholesterol.Cholesterol efflux was initiated by adding the 10 μg/ml ApoA-I(CalBiochem, La Jolla, Calif.), with or without Compound 2 (1 μM finalconcentration) in serum free media. Compound 2 was added to culturedcells from stock solution, and control cells received an equivalentamount of vehicle. After 24 hr, media were harvested and cells weredissolved in 1 mM HEPES, pH 7.5 containing 0.5% of a detergent TritonX-100 (Sigma, St-Louis, Mo.). Media were briefly centrifuged to removenon-adherent cells, and then aliquots of both the supernatant and thedissolved cells were counted by liquid scintillation spectrometry todetermine radioactivity.

Cholesterol efflux is expressed as a percentage, calculated as([3H]Cholesterol in medium)/([3H]Cholesterol in medium+[3H]cholesterolin cells)×100

As shown in FIG. 4, compound 2 increases cholesterol efflux from THP-1cells as compared to non treated cells.

Example 30 Oral Administration of Selected Compounds in the Treatment ofDiet-Induced Hypercholesterolemia in Wild Type Sprague Dawley Rats (SeeResults in FIGS. 5 a-c)

Experimental Procedure: Six week-old male Sprague Dawley rats (obtainedfrom Harlan of San Diego, Calif.) were housed in a fixed 12-12-hrartificial light-dark cycle, and maintained on a high cholesterolatherogenic diet (Paigen's Diet, obtained from Research Diet Inc. of NewBrounswick, N.J.) was provided ad libitum. Animals were allowed six daysto acclimate in this experimental environment prior to the initiation ofthe study.

Prior to initiation of treatment, the animals were bled from the tailvein (100-200mL of whole blood) and serum levels of cholesterol weremeasured in duplicate (Cholesterol Infinity kits; Sigma, St. Louis,Mo.). Based on these initial measures, animals were sorted into groupswith approximately the same average total cholesterol levels. Oncesorted, the animals were housed three per cage and maintained onPaigen's diet ad libitum. All compounds to be tested were suspended insesame oil and administered in a final volume of 3 ml/kg. Drug isadministered by oral gavage once daily at the beginning of theartificial light cycle. To obtain a base line for lipid measurement, acontrol group maintained on standart rodent diet is included (leancontrol).

Treatment Group A (n=6/group): (See Results in FIG. 5 a)

-   -   1) Lean control (Sesame Oil)    -   2) Control    -   3) Compound 2 (0.3 mg/kg)    -   4) Compound 2 (1 mg/kg)    -   5) Compound 2 (3 mg/kg)

Treatment Group B (n=6/group): (See Results in FIG. 5 b)

-   -   1) Lean control (Sesame Oil)    -   2) Control    -   3) Compound 6 (3 mg/kg)

Treatment Group C (n=6/group): (See Results in FIG. 5 c)

-   -   1) Lean control (10% HPPCD)    -   2) Control    -   3) Compound 25 (1 mg/kg)    -   4) Compound 25 (3 mg/kg)    -   5) Compound 25 (10 mg/kg)    -   6) Compound 25 (15 mg/kg)    -   The compounds were dissolved in a 10% hydroxy propyl beta        cyclodextrin solution, and administered to animals in a volume        of 10 ml/kg/dose.

To monitor the effect of the tested compounds, animals were bled fromthe tail vein at the end of the dark cycle on days 0 (for sorting) andday 5 of the treatment period. Fed serum cholesterol levels weremeasured in duplicate. The blood is kept at room temperature to allowcoagulation, after which the serum is separated and assayed for totalcholesterol (Infinity reagent, Sigma), HDL cholesterol (using HDLprecipitating reagent and infinity reagent, Sigma) and LDL cholesterol(EzLDL kit, Sigma). As shown in FIGS. 5 a-c, all compounds tested showsignificant reduction in total and LDL cholesterol levels and asignificant increase in HDL cholesterol levels compared to high fat fedcontrol animals.

Example 31 Oral Administration of Selected Compounds Slows theProgression of Mammary Tumors in Sprague Dawley Rats (See Results inFIG. 6)

Procedure: Five week-old female Sprague Dawley rats (Harlan) were housedin a fixed 12-12-hr artificial light-dark cycle, and maintained on astandard rodent diet provided ad libitum. Animals were allowed two daysto acclimate in this experimental environment prior to the initiation ofthe study. To induce mammary tumors, the female mice were injectedintraperitoneally with the carcinogen n-nitroso-n-methylurea, in asingle dose of 50 mg/kg in acidified normal saline (pH4 w/acetic acid)at a final volume of 10 mg/ml (5 ml/kg). After eight weeks, mammarytumors are detected, and the tumor bearing females are sorted intotreatment groups. Once sorted, the animals were housed four per cage andprovided rodent diet ad libitum. All animals are treated with compound 1or a vehicle for four weeks, during which time changes in tumor size aremonitored. Tumors were classified as regressing, static or progressing.

Treatment groups (n=8/group):

-   -   1) Control (sesame oil)    -   2) Compound 6 (20 mg/kg)    -   3) Compound 11 (100 mg/kg)    -   4) Compound 13 (50 mg/kg)    -   5) Compound 24 (50 mg/kg)    -   6) Compound 25 (20 mg/kg)    -   7) Compound 25 (100 mg/kg)

All of the compounds tested were suspended in sesame oil, andadministered to animals in a volume of 3 ml/kg/dose, except compound 25which was dissolved in a 10% hydroxy propyl beta cyclodextrin solution,and administered to animals in a volume of 10 m/kg/dose. All treatmentswere administered by oral gavage once daily for four weeks.

To monitor the effect of the tested compound, animals were examined formammary tumors once every week. Tumors were classified into one of threecategories, progressing, static or regressing. All of the compoundstested slowed the progression of mammary tumors compared to vehicletreated controls as shown in FIG. 6. Nevertheless, some of the compoundsshowed greater efficacy in this model. For example, Compound 25 causedthe regression of tumors at doses as low as 20 mg/kg, whereas, compounds11 and 13 only increase the number of static tumors (tumors that do notchange in volume over the course of the study) compared to controlanimals without causing any regressions.

Example 32 A Comparison of Oral Bioavailability between Compound 24 andCompound 25 (See Results in FIG. 7)

Six to eight week-old male Sprague Dawley rats (Harlan) were housed in afixed 12-12-hr artificial light-dark cycle, and maintained on a standardrodent diet provided ad libitum. Animals were allowed two days toacclimate in this experimental environment prior to the initiation ofthe study. Compounds 24 and 25 were dissolved in a 10% hydroxypropylbeta cyclodextrin solution and administered by oral gavage in a finaldose of 10 mg/kg in a volume of 5 ml/kg. Treatment groups were dividedas follows:

Treatment groups (n=3/group):

-   -   1) Compound 24 (10 mg/kg)    -   2) Compound 25 (10 mg/kg)

Each animal received a single treatment, after which, the animal wasbled from the tail vein at the following time points: 0.5, 1, 2, 4, 6,9, 12, and 26 hours after treatment. To measure the concentration ofeach compound in plasma, blood samples were collected in heparin-coatedtubes, and the plasma was isolated and analyzed by HPLC. Compound 25 waspresent at a significantly higher concentration as compared to compound24, which was only detected as being present at near the limit ofdetection in the plasma samples (FIG. 7). This highlights the improvedbioavailability and pharmaceutical properties of Compound 25 overCompound 24.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

1. A method of treating type 2 Diabetes comprising administering to amammal diagnosed as needing such treatment one or more compounds acompound of Formula (200):

wherein: a) the B, H, I, J and K residues are independently selectedfrom —C(O)—, —C(S)—, —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—,—C(R₁₀₅)(R₁₀₆), or —C(R₁₀₇)(R₁₀₈)— residues, and from zero to two of theB, H, I, J or K residues can be absent; wherein: i) R₁₀₁, R₁₀₂, R₁₀₃,R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇ and R₁₀₈ are independently selected fromhydrogen, hydroxyl, a halogen, amino, or an organic residue comprising 1to 12 carbon atoms; or two of the R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆,R₁₀₇ and R₁₀₈ residues can be connected together to form an exocyclicsubstituent residue comprising 1 to 6 ring carbon atoms and from 0 to 3optional ring heteroatoms selected from O, S, or N; and ii) B, H, I, Jand K together with the Ar₅ form a ring containing at least one amideresidue having the formula

 wherein R_(x) is a R₁₀₁ or R₁₀₂ residue; b) Ar₅ is an aryl, substitutedaryl, heteroaryl, or substituted heteroaryl residue comprising from 3 to6 ring carbon atoms and from 0 to 3 optional ring heteroatoms selectedfrom O, S, or N; c) Ar₆ is an aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl residue comprising from 2 to 6 ring carbon atomsand from 0 to 3 optional ring heteroatoms selected from O, S, or N; d)R₁₀₉ is hydrogen, hydroxy, or an organic residue comprising 1 to 10carbon atoms; e) ----- is either present or absent; f) W, X, Y and Zform a 2,4-thiazolidinedione, 2-thioxo-thiazolidine-4-one,2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one residue; or apharmaceutically acceptable salt thereof, in an amount effective totreat type 2 diabetes.
 2. The method of claim 1 wherein the radical:

has the structure:

wherein R₁₀₁ is selected from hydrogen or an organic radical comprising1 to 12 carbon atoms, and wherein R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, and R₁₁₀ areindependently selected from hydrogen or alkyls comprising 1 to 4 carbonatoms.
 3. The method of claim 1 wherein the radical:

has the structure:

wherein R₁₀₁, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, and R₁₁₀ are independentlyselected from hydrogen or alkyls comprising 1 to 4 carbon atoms.
 4. Themethod of claim 1 wherein the radical:

has the structure:

wherein R₁₀₁ and R₁₁₀ are an alkyl comprising 1 to 4 carbon atoms. 5.The method of claim 1 wherein Ar₆ comprises a phenyl ring.
 6. The methodof claim 5 wherein the Ar₆ ring is substituted with one, two or threesubstituents independently selected from halogens or a radicalcomprising 1 to 4 carbon atoms selected from an alkyl, a haloalkyl, anamino, a mono-substituted amino, a di-substituted amino, an alkoxy, or ahaloalkoxy.
 7. The method of claim 1 wherein Ar₆ comprises a pyridylring.
 8. The method of claim 7 wherein the Ar₆ ring is substituted withone, two or three substituents independently selected from halogens or aradical comprising 1 to 4 carbon atoms selected from an alkyl, ahaloalkyl, an amino, a mono-substituted amino, a di-substituted amino,an alkoxy, or a haloalkoxy.
 9. The method of claim 1 wherein Ar₆ has thestructure:

wherein R₁₂₅, R₁₂₆, R₁₂₇ and R₁₂₈ are substituents independentlyselected from hydrogen, halogen, nitro, hydroxyl, amino, or an organicradical comprising 1 to 4 carbon atoms.
 10. The method of claim 9wherein R₁₂₅ is not hydrogen.
 11. The method of claim 10 wherein R₁₂₅ isan alkyl, substituted alkyl, haloalkyl, alkoxy, substituted alkoxy,haloalkoxy, halogen, amino, mono-substituted amino, or disubstitutedamino radical comprising 1 to four carbons.
 12. The method of claim 1wherein Ar₆ has the structure:

wherein R₁₂₆, R₁₂₇ and R₁₂₈ are independently or together hydrogen orhalogen.
 13. The method of claim 1 wherein ----- is present.
 14. Themethod of claim 1 wherein R₁₀₉ is hydrogen.
 15. The method of claim 1wherein the heterocycle comprising W, X, Y and Z has the structure


16. The method of claim 1 in the form of a salt wherein the heterocyclecomprising W, X, Y and Z forms an anion having the structure:


17. A method of treating breast cancer comprising administering to amammal diagnosed as needing such treatment a compound having the formula5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,or a pharmaceutically acceptable salt thereof, in an amount effective totreat breast cancer.
 18. A method of treating Type 2 Diabetes comprisingadministering to a human diagnosed as needing such treatment, a compoundhaving the formula5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dioneor a pharmaceutically acceptable salt thereof, in an amount effective todecrease serum glucose levels by at least about 5% and also decreaseserum triglyeride levels by at least about 5%.
 19. A method of treatinghypercholesterolemia comprising administering to a mammal diagnosed asneeding such treatment one or more compounds having the structure:

wherein a) Ar₅ is an aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; b) B, H, I, J and K are independently selected from —C(O)—,—C(S), —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—, —C(R₁₀₅)(R₁₀₆)—,or —C(R₁₀₇)(R₁₀₈)—, wherein one, or two of B, H, I, J or K canoptionally be absent; and i) R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇and R₁₀₈ are independently selected from hydrogen, hydroxyl, a halogen,amino, or an organic radical comprising 1 to 12 carbon atoms; ii) two ofB, H, I, J and K form at least one radical having the structure:

 wherein R_(x) is a R₁₀₁ or R₁₀₂ radical; iii) Ar₅ together with B, H,I, J and K comprise from 2 to 24 carbon atoms; c) Ar₆ is an aryl,substituted aryl, heteroaryl, or substituted heteroaryl comprising from2 to 18 carbon atoms; d) R₁₀₉ is hydrogen, hydroxy, or an organicradical comprising 1 to 10 carbon atoms; e) ----- is either present orabsent; f) HAr is a heterocycle having the structure:

or a pharmaceutically acceptable salt thereof.
 20. The method of claim19 wherein the one or more compounds or salts are applied in an amounteffective to decrease serum cholesterol levels by at least about 5%. 21.A method of treating dyslipidemia comprising administering to a mammaldiagnosed as needing such treatment one or more compounds having thestructure:

wherein a) Ar₅ is an aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; b) B, H, I, J and K are independently selected from —C(O)—,—C(S), —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—, —C(R₁₀₅)(R₁₀₆)—,or —C(R₁₀₇)(R₁₀₈)—, wherein one, or two of B, H, I, J or K canoptionally be absent; and i) R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇and R₁₀₈ are independently selected from hydrogen, hydroxyl, a halogen,amino, or an organic radical comprising 1 to 12 carbon atoms; ii) two ofB, H, I, J and K form at least one radical having the structure:

 wherein R_(x) is a R₁₀₁ or R₁₀₂ radical; iii) Ar₅ together with B, H,I, J and K comprise from 2 to 24 carbon atoms; c) Ar₆ is an aryl,substituted aryl, heteroaryl, or substituted heteroaryl comprising from2 to 18 carbon atoms; d) R₁₀₉ is hydrogen, hydroxy, or an organicradical comprising 1 to 10 carbon atoms; e) ----- is either present orabsent; f) HAr is a heterocycle having the structure:

or a pharmaceutically acceptable salt thereof, in an amount effective todecrease serum triglyceride levels in the animal.
 22. The method ofclaim 21, wherein the one or more compounds or salts are applied in anamount effective to decrease triglyceride levels by at least about 5%.23. A method of treating type 2 Diabetes comprising administering to amammal diagnosed as needing such treatment one or more compounds havingthe structure:

wherein a) Ar₅ is an aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; b) B, H, I, J and K are independently selected from —C(O)—,—C(S), —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—, —C(R₁₀₅)(R₁₀₆)—,or —C(R₁₀₇)(R₁₀₈)—, wherein one, or two of B, H, I, J or K canoptionally be absent; and i) R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇and R₁₀₈ are independently selected from hydrogen, hydroxyl, a halogen,amino, or an organic radical comprising 1 to 12 carbon atoms; ii) two ofB, H, I, J and K form at least one radical having the structure

 wherein R_(x) is a R₁₀₁ or R₁₀₂ radical; iii) Ar₅ together with B, H,I, J and K comprise from 2 to 24 carbon atoms; c) Ar₆ is an aryl,substituted aryl, heteroaryl, or substituted heteroaryl comprising from2 to 18 carbon atoms; d) R₁₀₉ is hydrogen, hydroxy, or an organicradical comprising 1 to 10 carbon atoms; e) ----- is either present orabsent; f) HAr is a heterocycle having the structure:

or a pharmaceutically acceptable salt thereof, in an amount effective totreat type 2 diabetes.
 24. The method of claim 23, wherein the one ormore compounds or salts are applied in an amount effective to decreaseblood glucose levels by at least about 5%.
 25. A method of treating Type2 Diabetes comprising administering to a human diagnosed as needing suchtreatment one or more compounds having the structure:

wherein a) Ar₅ is an aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; b) B, H, I, J and K are independently selected from —C(O)—,—C(S)—, —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—,—C(R₁₀₅)(R₁₀₆)—, or —C(R₁₀₇)(R₁₀₈)—, wherein one, or two of B, H, I, Jor K can optionally be absent; and i) R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅,R₁₀₆, R₁₀₇ and R₁₀₈ are independently selected from hydrogen, hydroxyl,a halogen, amino, or an organic radical comprising 1 to 12 carbon atoms;ii) two of B, H, I, J and K form at least one radical having thestructure:

 wherein R_(x) is a R₁₀₁ or R₁₀₂ radical; iii) Ar₅ together with B, H,I, J and K comprise from 2 to 24 carbon atoms; c) Ar₆ is an aryl,substituted aryl, heteroaryl, or substituted heteroaryl comprising from2 to 18 carbon atoms; d) R₁₀₉ is hydrogen, hydroxy, or an organicradical comprising 1 to 10 carbon atoms; e) ----- is either present orabsent; f) HAr is a heterocycle having the structure:

or a pharmaceutically acceptable salt thereof, in an amount effective todecrease serum glucose levels by at least about 5% and also decreaseserum triglyeride levels by at least about 5%.
 26. A method of treatingbreast cancer comprising administering to a mammal diagnosed as needingsuch treatment one or more compounds having the structure:

wherein a) Ar₅ is an aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; b) B, H, I, J and K are independently selected from —C(O)—,—C(S)—, —O—, —S—, —N(R₁₀₁)—, —N(R₁₀₂)—, —C(R₁₀₃)(R₁₀₄)—,—C(R₁₀₅)(R₁₀₆)—, or —C(R₁₀₇)(R₁₀₈)—, wherein one, or two of B, H, I, Jor K can optionally be absent; and i) R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅,R₁₀₆, R₁₀₇ and R₁₀₈ are independently selected from hydrogen, hydroxyl,a halogen, amino, or an organic radical comprising 1 to 12 carbon atoms;ii) two of B, H, I, J and K form at least one radical having thestructure:

 wherein R_(x) is a R₁₀₁ or R₁₀₂ radical; iii) Ar₅ together with B, H,I, J and K comprise from 2 to 24 carbon atoms; c) Ar₆ is an aryl,substituted aryl, heteroaryl, or substituted heteroaryl comprising from2 to 18 carbon atoms; d) R₁₀₉ is hydrogen, hydroxy, or an organicradical comprising, 1 to 10 carbon atoms; e) ----- is either present orabsent; f) HAr is a heterocycle having the structure:

or a pharmaceutically acceptable salt thereof, in an amount effective totreat the breast cancer.